Benzamidine derivatives and their use as anti-coagulants

ABSTRACT

PCT No. PCT/US96/02641 Sec. 371 Date Dec. 8, 1997 Sec. 102(e) Date Dec. 8, 1997 PCT Filed Mar. 8, 1996 PCT Pub. No. WO96/28427 PCT Pub. Date Sep. 19, 1996This invention is directed to benzamidine derivatives which are useful as anti-coagulants. This invention is also directed to pharmaceutical compositions containing the compounds of the invention, and methods of using the compounds to treat disease-states characterized by thrombotic activity.

CROSS-REFERENCE

This application is a 371 of PCT/US96/02,641 filed Mar. 8, 1996.

FIELD OF THE INVENTION

The present invention is directed to benzamidine derivatives and theirpharmaceutically acceptable salts, which inhibit the enzyme, factor Xa,thereby being useful as anti-coagulants. It also relates topharmaceutical compositions containing the derivatives or theirpharmaceutically acceptable salts, and methods of their use.

BACKGROUND OF THE INVENTION

Factor Xa is a member of the trypsin-like serine protease class ofenzymes. A one-to-one binding of factors Xa and Va with calcium ions andphospholipid forms the prothrombinase complex which converts prothrombinto thrombin. Thrombin, in turn, converts fibrinogen to fibrin whichpolymerizes to form insoluble fibrin.

In the coagulation cascade, the prothrombinase complex is the convergentpoint of the intrinsic (surface activated) and extrinsic (vesselinjury-tissue factor) pathways (Biochemistry (1991), Vol. 30, p. 10363;and Cell (1988), Vol. 53, pp. 505-518). The model of the coagulationcascade has been refined further with the discovery of the mode ofaction of tissue factor pathway inhibitor (TFPI) (Seminars in Hematology(1992), Vol. 29, pp. 159-161). TFPI is a circulating multi-domain serineprotease inhibitor with three Kunitz-like domains which competes withfactor Va for free factor Xa. Once formed, the binary complex of factorXa and TFPI becomes a potent inhibitor of the factor VIIa and tissuefactor complex.

Factor Xa can be activated by two distinct complexes, by tissuefactor-VIIa complex on the "Xa burst" pathway and by the factorIXa-VIIIA complex (TENase) of the "sustained Xa" pathway in thecoagulation cascade. After vessel injury, the "Xa burst" pathway isactivated via tissue factor (TF). Up regulation of the coagulationcascade occurs via increased factor Xa production via the "sustained Xa"pathway. Down regulation of the coagulation cascade occurs with theformation of the factor Xa-TFPI complex, which not only removes factorXa but also inhibits further factor formation via the "Xa burst"pathway. Therefore, the coagulation cascade is naturally regulated byfactor Xa.

The primary advantage of inhibiting factor Xa over thrombin in order toprevent coagulation is the focal role of factor Xa versus the multiplefunctions of thrombin. Thrombin not only catalyzes the conversion offibrinogen to fibrin, factor VIII to VIIIA, factor V to Va, and factorXI to XIa, but also activates platelets, is a monocyte chemotacticfactor, and mitogen for lymphocytes and smooth muscle cells. Thrombinactivates protein C, the in vivo anti-coagulant inactivator of factorsVa and VIIIa, when bound to thrombomodulin. In circulation, thrombin israpidly inactivated by antithrombin III (ATIII) and heparin cofactor II(HCII) in a reaction which is catalyzed by heparin or otherproteolycan-associated glycosaminoglycans, whereas thrombin in tissuesis inactivated by the protease, nexin. Thrombin carries out its multiplecellular activation functions through a unique "tethered ligand"thrombin receptor (Cell (1991), Vol. 64, p. 1057), which requires thesame anionic binding site and active site used in fibrinogen binding andcleavage and by thrombomodulin binding and protein C activation. Thus, adiverse group of in vivo molecular targets compete to bind thrombin andthe subsequent proteolytic events will have very different physiologicalconsequences depending upon which cell type and which receptor,modulator, substrate or inhibitor binds thrombin.

Published data with the proteins antistasin and tick anti-coagulantpeptide (TAP) demonstrate that factor Xa inhibitors are efficaciousanti-coagulants (Thrombosis and Haemostasis (1992), Vol. 67, pp.371-376; and Science (1990), Vol. 248, pp. 593-596).

The active site of factor Xa can be blocked by either a mechanism-basedor a tight binding inhibitor (a tight binding inhibitor differs from amechanism-based inhibitor by the lack of a covalent link between theenzyme and the inhibitor). Two types of mechanism-based inhibitors areknown, reversible and irreversible, which are distinguished by ease ofhydrolysis of the enzyme-inhibitor link (Thrombosis Res (1992), Vol. 67,pp. 221-231; and Trends Pharmacol Sci. (1987), Vol. 8, pp. 303-307). Aseries of guanidino compounds are examples of tight-binding inhibitors(Thrombosis Res. (1980), Vol. 19, pp. 339-349).Arylsulfonyl-arginine-piperidinecarboxylic acid derivatives have alsobeen shown to be tight-binding inhibitors of thrombin (Biochem. (1984),Vol. 23, pp. 85-90), as well as a series of arylamidine-containingcompounds, including 3-amidinophenylaryl derivatives (Thrombosis Res.(1983), Vol. 29, pp. 635-642) and bis(amidino)benzyl cycloketones(Thrombosis Res. (1980), Vol. 17, pp. 545-548). However, these compoundsdemonstrate poor selectivity for factor Xa.

RELATED DISCLOSURES

European Published Patent Application 0 540 051 (Nagahara et al.)describes aromatic amidine derivatives which are stated to be capable ofshowing a strong anticoagulant effect through reversible inhibition offactor Xa.

The synthesis of α,α'-bis(amidinobenzylidene)cycloalkanones andα,α'-bis(amidino-benzyl)cycloalkanones is described in Pharmazie (1977),Vol. 32, No. 3, pp. 141-145. These compounds are disclosed as beingserine protease inhibitors.

SUMMARY OF THE INVENTION

This invention is directed to compounds or their pharmaceuticallyacceptable salts which inhibit human factor Xa and are therefore usefulas pharmacological agents for the treatment of disease-statescharacterized by thrombotic activity.

Accordingly, in one aspect, this invention provides compounds selectedfrom the group consisting of the following formulae: ##STR1## wherein Ais --C(R¹¹)═ or --N═;

Z¹ and Z² are independently --O--, --N(R⁸)--, --S--,or --OCH₂ --;

R¹ and R³ are independently hydrogen, halo, alkyl, haloalkyl, alkoxy,haloalkoxy, nitro, --N(R⁸)R⁹, --C(O)OR⁸, --C(O)N(R⁸)R⁹, --C(O)N(R⁸)CH₂C(O)N(R⁸ (R⁹, --N(R⁸)C(O)N(R⁸)R⁹, --N(R⁸)C(O)R⁸, --N(R⁸)S(O)₂ R¹², or--N(R⁸)C(O)N(R⁸)CH₂ C(O)N(R⁸)R⁹ ;

R² is hydrogen; halo; alkyl; haloalkoxy; --OR⁸ ; --C(O)OR⁸ ;--C(O)N(R⁸)R⁹ ; --N(R⁸)R⁹ ; --C(O)N(R⁸)(CH₂)_(m) C(O)OR⁸ (where m is 0to 3); --N(R⁸)(CH₂)_(n) C(O)OR⁸ (where n is 1 to 3); --N((CH₂)_(n)N(R⁸)R⁹)(CH₂)_(n) C(O)OR⁸ (where each n is 1 to 3); --O(CH₂)_(n)C(O)N(R⁸)R⁹ (where n is 1 to 3); --O(CH₂)_(p) C(O)OR⁸ (where p is 1 to6); --N(R⁸)(CH₂)_(n) C(O)N(R⁸)(CH₂)_(n) C(O)OR⁸ (where each n isindependently 1 to 3); morpholin-4-yl; 3-tetrahydrofuranoxy;

or R² is aryloxy (optionally substituted by one or more substituentsindependently selected from the group consisting of --OR⁸,--C(O)N(R⁸)R⁹, halo, alkyl, carboxy, alkoxycarbonyl, haloalkoxy,haloalkoxycarbonyl, alkoxycarbonylalkyl, carboxyalkyl,aminocarbonylalkyl, (alkylamino)carbonylalkyl,(dialkylamino)carbonylalkyl, (arylamino)carbonylalkyl,(aralkylamino)carbonylalkyl, alkoxycarbonylalkenyl, carboxyalkenyl,aminocarbonylalkenyl, (alkylamino)carbonylalkenyl,(dialkylamino)carbonylalkenyl, (arylamino)carbonylalkenyl,(aralkylamino)carbonylalkenyl, (hydroxyalkoxy)carbonyl,(alkoxy)alkoxycarbonyl, (hydroxyalkoxy)alkoxycarbonyl,((alkoxy)alkoxy)alkoxycarbonyl, tetrazolyl, morpholin-4-ylalkyl, and(1,2)-imidazolinyl (optionally substituted by alkyl));

or R² is piperazin-1-yl (optionally substituted by one or moresubstituents independently selected from the group consisting of alkyl,carboxy, --C(O)N(R⁸)R⁹, carboxyalkyl, alkoxycarbonyl, andalkoxycarbonylalkyl);

or R² is 1-piperazinoyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, carboxy,--C(O)N(R⁸)R⁹, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl);

or R² is piperidin-1-yl (optionally substituted by one or moresubstituents selected from the group consisting of carboxy,--C(O)N(R⁸)R⁹, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl);

or R² is (3,4)-piperidinyloxy (optionally substituted by one or moresubstituents selected from the group consisting of alkylcarbonyl,carboxy, --C(O)N(R⁸)R⁹, alkoxycarbonyl, carboxyalkyl,alkoxycarbonylalkyl, and tetrazolylalkyl);

or R² is piperidin-4-ylamino (wherein the amino is optionallysubstituted by alkyl and the piperidinyl group is optionally substitutedby one or more substituents selected from the group consisting of alkyl,alkoxycarbonyl, --C(O)N(R⁸) R⁹, carboxyalkyl, alkoxycarbonylalkyl andaralklyl);

or R² is 3-pyrrolidinyloxy (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aralkyl,amidino, 1-iminoethyl, carboxy, --C(O)N(R⁸)R⁹, carboxyalkyl,alkoxycarbonyl and alkoxycarbonylalkyl);

R⁴ and R⁷ are independently hydrogen, halo, alkyl, nitro, --OR⁸,--C(O)OR⁸, --C(O)N(R⁸)R⁹, --N(R⁸)R⁹, --N(H)C(O)R⁸, or --N(H)S(O)₂ R¹² ;

R⁵ is --C(NH)NH₂, --C(NH)N(H)OR⁸, --C(NH)N(H)C(O)OR¹², --C(NH)N(H)S(O)₂R¹², --C(NH)N(H)C(O)N(R⁸)R⁹, or --C(NH)N(H)C(O)R⁸ ;

R⁶ is halo, alkyl, haloalkyl, haloalkoxy, nitro, amino, ureido,guanidino, --OR⁸, --C(NH)NH₂, --C(NH)NHOH, --C(O)R¹⁰, --(CH₂)_(m)C(O)N(R⁸)R⁹ (where m is 0 to 3), --CH(OH)C(O)N(R⁸)R⁹, --(CH₂)_(m)N(R⁸)R⁹ (where m is 0 to 3), --(CH₂)_(m) C(O)OR⁸ (where m is 0 to 3),--N(H)C(O)R⁸, (1,2)-tetrahydropyrimidinyl (optionally substituted byalkyl), (1,2)-imidazolyl (optionally substituted by alkyl), or(1,2)-imidazolinyl (optionally substituted by alkyl);

each R⁸ and R⁹ is independently hydrogen, alkyl, aryl, or aralkyl;

R¹⁰ is hydrogen, alkyl, aryl, aralkyl, 1-pyrrolidinyl, 4-morpolinyl,4-piperazinyl, 4-(N-methyl)piperazinyl, or piperidin-1-yl;

R¹¹ is hydrogen, alkyl or halo; and

R¹² is alkyl, aryl or aralkyl;

or a pharmaceutically acceptable salt thereof.

In another aspect, this invention provides compositions useful intreating a human having a disease-state characterized by thromboticactivity, which composition comprises a therapeutically effective amountof a compound of the invention as described above, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient.

In another aspect, this invention provides a method of treating a humanhaving a disease-state characterized by thrombotic activity, whichmethod comprises administering to a human in need thereof atherapeutically effective amount of a compound of the invention asdescribed above.

In another aspect, this invention provides a method of treating a humanhaving a disease-state alleviated by the inhibition of factor Xa, whichmethod comprises administering to a human in need thereof atherapeutically effective amount of a compound of the invention asdescribed above.

In another aspect, this invention provides a method of inhibiting humanfactor Xa in vitro or in vivo by the administration of a compound of theinvention.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated:

"Halo" refers to bromo, chloro or fluoro.

"Aminocarbonyl" refers to the radical --C(O)NH₂.

"Amidino" refers to the radical --C(NH)NH₂.

"Benzamidine" refers to a phenyl radical substituted by an amidinoradical.

"Carboxy" refers to the radical --C(O)OH.

"Dimethylaminocarbonyl" refers to the radical --C(O)N(CH₃)₂.

"Alkyl" refers to a straight or branched chain monovalent or divalentradical consisting solely of carbon and hydrogen, containing nounsaturation and having from one to six carbon atoms, e.g., methyl,ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl,1,1-dimethylethyl (t-butyl), and the like.

"Alkenyl" refers to a straight or branched chain monovalent or divalentradical consisting solely of carbon and hydrogen, containing at leastone double bond and having from one to six carbon atoms, e.g., ethenyl,prop-1-enyl, but-1-enyl, pent-1-enyl, pent-1,4-dienyl, and the like.

"Haloalkyl" refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, trichloromethyl, 2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl,1-bromomethyl-2-bromoethyl, and the like.

"Haloalkoxy" refers to a radical of the formula --OR_(b) wherein R_(b)is haloalkyl as defined above, e.g., trifluoromethoxy, difluoromethoxy,trichloromethoxy, 2-trifluoroethoxy, 1-fluoromethyl-2-fluoroethoxy,3-bromo-2-fluoropropoxy, 1-bromomethyl-2-bromoethoxy, and the like.

"Aryl" refers to a phenyl or naphthyl radical optionally substituted byhalo, alkyl, alkoxy, amino, nitro or carboxy.

"Aralkyl" refers to a radical of the formula --R_(a) R_(c) where R_(a)is alkyl as defined above and R_(c) is aryl as defined above, e.g.,benzyl.

"Aryloxy" refers to a radical of the formula --OR_(c) where R_(c) isphenyl or naphthyl, e.g., phenoxy and naphthoxy.

"Alkoxy" refers to a radical of the formula --OR_(a) where R_(a) isalkyl as defined above, e.g., methoxy, ethoxy, n-propoxy, 1-methylethoxy(iso-propoxy), n-butoxy, n-pentoxy, 1,1-dimethylethoxy (t-butoxy), andthe like.

"Alkanol" refers to a branched or unbranched aliphatic hydrocarbon of 1to 6 carbons wherein one hydroxyl radical is attached thereto, e.g.,methanol, ethanol, isopropanol, and the like.

"Aminocarbonylalkyl" refers to a radical of the formula --R_(a) C(O)NH₂wherein R_(a) is alkyl as defined above, e.g., aminocarbonylmethyl,2-aminocarbonylethyl, 3-aminocarbonylpropyl,1,1-dimethyl-2-aminocarbonylethyl, and the like.

"(Alkylamino)carbonylalkyl" refers to a radical of the formula --R_(a)C(O)N(H)R_(a) wherein each R_(a) is the same or different and is alkylas defined above, e.g., (methylamino)carbonylmethyl,2-(ethylamino)carbonylethyl, 3-(methylamino)-carbonylpropyl,1,1-dimethyl-2-(ethylamino)carbonylethyl, and the like.

"(Dialkylamino)carbonylalkyl" refers to a radical of the formula --R_(a)C(O)N(R_(a))₂ wherein each R_(a) is the same or different and is alkylas defined above, e.g., (dimethylamino)carbonylmethyl,2-(diethylamino)carbonylethyl, 3-(dimethylamino)carbonylpropyl,1,1-dimethyl-2-(diethylamino)carbonylethyl, and the like.

"(Arylamino)carbonylalkyl" refers to a radical of the formula --R_(a)C(O)N(H)R_(c) wherein R_(a) is alkyl as defined above and R_(c) is arylas defined above, e.g., phenylaminocarbonylmethyl,2-phenylaminocarbonylethyl, 3-phenylaminocarbonylpropyl,1,1-dimethyl-2-phenylaminocarbonylethyl, and the like.

"(Aralkylamino)carbonylalkyl" refers to a radical of the formula --R_(a)C(O)N(H)R_(c) wherein R_(a) is alkyl as defined above and R_(d) isaralkyl as defined above, e.g., benzylaminocarbonylmethyl,2-benzylaminocarbonylethyl, 3-benzylaminocarbonylpropyl,1,1-dimethyl-2-benzylaminocarbonylethyl, and the like.

"Alkoxycarbonylalkenyl" refers to a radical of the formula --R_(e)C(O)OR_(a) wherein R_(a) is lower alkyl as defined above and R_(e) isalkenyl as defined above, e.g., 2-methoxycarbonylethenyl,3-methoxycarbonyprop-1-enyl, 2-ethoxycarbonylethenyl, and the like.

"Carboxyalkenyl" refers to a radical of the formula --R_(e) C(O)OH whereR_(e) is alkenyl as defined above, e.g., 2-carboxyethenyl,3-carboxyprop-1-enyl, 4-carboxybut-1-enyl, and the like.

"Aminocarbonylalkenyl" refers to a radical of the formula --R_(e)C(O)NH₂ wherein R_(e) is alkenyl as defined above, e.g.,2-aminocarbonylethenyl, 3-aminocarbonylprop-1-enyl,1-methyl-2-aminocarbonylethenyl, and the like.

"(Alkylamino)carbonylalkenyl" refers to a radical of the formula --R_(e)C(O)N(H)R_(a) wherein R_(a) is alkyl as defined above and R_(e) isalkenyl as defined above, e.g., 2-(ethylamino)carbonylethenyl,3-(methylamino)carbonylprop-1-enyl,1-methyl-2-(ethylamino)carbonylethenyl, and the like.

"(Dialkylamino)carbonylalkenyl" refers to a radical of the formula--R_(e) C(O)N(R_(a))₂ wherein each R_(a) is the same or different and isas defined above and R_(e) is alkenyl as defined above, e.g.,2-(diethylamino)carbonylethenyl, 3-(dimethylamino)carbonylprop-1-enyl,1-methyl-2-(diethylamino)carbonylethenyl, and the like.

"(Arylamino)carbonylalkenyl" refers to a radical of the formula --R_(e)C(O)N(H)R_(c) wherein R_(c) is aryl as defined above and R_(e) isalkenyl as defined above, e.g., 2-(phenylamino)carbonylethenyl,3-(phenylamino)carbonylprop-1-enyl,1-methyl-2-(phenylamino)carbonylethenyl, and the like.

"(Aralkylamino)carbonylalkenyl" refers to a radical of the formula--R_(e) C(O)N(H)R_(d) wherein R_(d) is aralkyl as defined above andR_(e) is alkenyl as defined above, e.g., 2-(benzylamino)carbonylethenyl,3-(benzylamino)carbonylprop-1-enyl,1-methyl-2-(benzylamino)carbonylethenyl, and the like.

"(Hydroxyalkoxy)carbonyl" refers to a radical of the formula--C(O)OR_(a) wherein R_(a) is alkyl as defined above substituted by ahydroxy radical, e.g., 2-(hydroxy)ethoxycarbonyl,3-(hydroxy)propoxycarbonyl, 5-(hydroxy)pentoxycarbonyl, and the like.

"(Alkoxy)alkoxycarbonyl" refers to a radical of the formula --C(O)OR_(a)OR_(a) wherein each R_(a) is the same or different and is alkyl asdefined above, e.g., 2-(methoxy)ethoxycarbonyl,3-(methoxy)propoxycarbonyl, 5-(ethoxy)pentoxycarbonyl, and the like.

"(Hydroxyalkoxy)alkoxycarbonyl" refers to a radical of the formula--C(O)OR_(a) OR_(a), wherein each R_(a) is the same or different and isalkyl as defined above, and the terminal R_(a) radical is substituted bya hydroxy radical, e.g., 2-(2-hydroxyethoxy)ethoxycarbonyl,2-(3-hydroxypropoxy)ethoxycarbonyl, and the like.

"((Alkoxy)alkoxy)alkoxycarbonyl" refers to a radical of the formula--C(O)OR_(a) OR_(a) OR_(a) where each R_(a) is the same or different andis alkyl as defined above, e.g., 2-(2-(methoxy)ethoxy)ethoxycarbonyl,3-(2-(methoxy)ethoxy)propoxycarbonyl,4-(3-ethoxy)propoxy)butoxycarbonyl, and the like.

"Haloalkoxycarbonyl" refers to a radical of the formula --C(O)OR_(b)wherein R_(b) is haloalkyl as defined above, e.g.,trifluoromethoxycarbonyl, difluoromethoxycarbonyl,trichloromethoxycarbonyl, 2-trifluoroethoxycarbonyl,1-fluoromethyl-2-fluoro-ethoxycarbonyl, 3-bromo-2-fluoropropoxycarbonyl,1-bromomethyl-2-bromoethoxy-carbonyl, and the like.

"Carboxyalkyl" refers to a radical of the formula --R_(a) C(O)OH whereR_(a) is alkyl as defined above, e.g., carboxymethyl, 2-carboxyethyl,3-carboxypropyl, and the like.

"Alkoxycarbonyl" refers to a radical of the formula --C(O)OR_(a) whereinR_(a) is alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl,n-propoxycarbonyl, and the like.

"Alkoxycarbonylalkyl" refers to a radical of the formula --R_(a)C(O)OR_(a) wherein each R_(a) is the same or different and is alkyl asdefined above, e.g., methoxycarbonylethyl, ethoxycarbonylethyl,t-butoxycarbonylethyl, and the like.

"Morpholin-4-ylalkyl" refers to a radical of the formula --R_(a) R_(f)where R_(a) is alkyl as defined above and R_(f) is a morpholin-4-ylradical, e.g., morpholin-4-ylmethyl, morpholin-4-ylethyl, and the like.

"4-morpholinoyl" refers to a radical of the formula --C(O)R_(f) whereR_(f) is a morpholin-4-yl radical.

"(3,4)-Piperidinyloxy" refers to a radical of the formula --OR_(g) whereR_(g) is a piperidinyl radical attached to the oxygen atom at either the3- or 4-position.

"3-Tetrahydrofuranyloxy" refers to the radical of the formula --OR_(h)where R_(h) is a tetrahydrofuranyl radical attached to the oxygen atomat the 3-position.

"3-Pyrrolidinyloxy" refers to the radical of the formula --OR_(i) whereR_(i) is a pyrrolidinyl radical attached to the oxygen atom at the3-position.

"1-Piperazinoyl" refers to the radical of the formula --C(O)R_(j) whereR_(j) is piperazin-1-yl.

"1-Piperidinoyl" refers to the radical of the formula --C(O)R_(k) whereR_(k) is piperidin-1-yl.

"1-Pyrrolidinoyl" refers to the radical of the formula --C(O)R_(m) whereR_(m) is pyrrolidin-1-yl.

"(1,2)-Imidazolyl" refers to an imidazolyl radical attached at eitherthe 1- or 2-position.

"(1,2)-Imidazolinyl" refers to a 4,5-dihydroimidazolyl radical attachedat either the 1- or the 2-position.

"DMSO" refers to dimethyl sulfoxide.

"HPLC" refers to high performance liquid chromatography.

"Optional" or "optionally" means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, "optionally substituted aryl" means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution.

"Pharmaceutically acceptable salt" includes both acid and base additionsalts.

"Pharmaceutically acceptable acid addition salt" refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid and the like, andorganic acids such as acetic acid, trifluoroacetic acid, propionic acid,glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid,succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, and the like.

"Pharmaceutically acceptable base addition salt" refers to those saltswhich retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Salts derived from inorganic bases include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine,ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine,procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particularly preferredorganic bases are isopropylamine, diethylamine, ethanolamine,trimethamine, dicyclohexylamine, choline and caffeine.

"Therapeutically effective amount" refers to that amount of a compoundof formula (I) which, when administered to a human in need thereof, issufficient to effect treatment, as defined below, for disease-statescharacterized by thrombotic activity. The amount of a compound offormula (I) which constitutes a "therapeutically effective amount" willvary depending on the compound, the disease-state and its severity, andthe age of the human to be treated, but can be determined routinely byone of ordinary skill in the art having regard to his own knowledge andto this disclosure.

"Treating" or "treatment" as used herein cover the treatment of adisease-state in a human, which disease-state is characterized bythrombotic activity; and include:

(i) preventing the disease-state from occurring in a human, inparticular, when such human is predisposed to the disease-state but hasnot yet been diagnosed as having it;

(ii) inhibiting the disease-state, i.e., arresting its development; or

(iii) relieving the disease-state, i.e., causing regression of thedisease-state.

The yield of each of the reactions described herein is expressed as apercentage of the theoretical yield.

The compounds of the invention, or their pharmaceutically acceptablesalts, may have asymmetric carbon atoms in their structure. Thecompounds of the invention and their pharmaceutically acceptable saltsmay therefore exist as single stereoisomers, racemates, and as mixturesof enantiomers and diastereomers. All such single stereoisomers,racemates and mixtures thereof are intended to be within the scope ofthis invention.

The nomenclature used herein is a modified form of the I.U.P.A.C. systemwherein the compounds of the invention are named as derivatives ofbenzamidine. For example, a compound of the invention selected fromformula (I), i.e., ##STR2## wherein A is --N═, Z¹ and Z² are both --O--,R¹ and R³ are both fluoro, R² is methyl, R⁴ is methoxy, R⁵ is--C(NH)NH₂, R⁶ is dimethylamino, and R⁷ is hydrogen, that is, a compoundof the following formula: ##STR3## is named herein as4-methoxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-methylpyridin-2-yl)oxy]benzamidine.

UTILITY AND ADMINISTRATION

A. Utility

The compounds of the invention are inhibitors of factor Xa and thereforeuseful in disease-states characterized by thrombotic activity based onfactor Xa's role in the coagulation cascade (see Background of theInvention above). A primary indication for the compounds is prophylaxisfor long term risk following myocardial infarction. Additionalindications are prophylaxis of deep vein thrombosis (DVT) followingorthopedic surgery or prophylaxis of selected patients following atransient ischemic attack. The compounds of the invention may also beuseful for indications in which coumadin is currently used, such as forDVT or other types of surgical intervention such as coronary arterybypass graft and percutaneous transluminal coronary angioplasty. Thecompounds are also useful for the treatment of thrombotic complicationsassociated with acute promyelocytic leukemia, diabetes, multiplemyelomas, disseminated intravascular coagulation associated with septicshock, purpura fulminanas associated infection, adult respiratorydistress syndrome, unstable angina, and thrombotic complicationsassociated with aortic valve or vascular prosthesis. The compounds arealso useful for prophylaxis for thrombotic diseases, in particular inpatients who have a high risk of developing such disease.

In addition, the compounds of the invention are useful as in vitrodiagnostic reagents for selectively inhibiting factor Xa withoutinhibiting other components of the coagulation cascade.

B. Testing

The primary bioassays used to demonstrate the inhibitory effect of thecompounds of the invention on factor Xa are simple chromogenic assaysinvolving only serine protease, the compound of the invention to betested, substrate and buffer (see, e.g., Thrombosis Res. (1979), Vol.16, pp. 245-254). For example, four tissue human serine proteases can beused in the primary bioassay, free factor Xa, prothrombinase, thrombin(IIa) and tissue plasminogen activator (tPA). The assay for tPA has beensuccessfully used before to demonstrate undesired side effects in theinhibition of the fibrinolytic process (see, e.g., J. Med. Chem. (1993),Vol. 36, pp. 314-319). Another bioassay useful in demonstrating theutility of the compounds of the invention in inhibiting factor Xademonstrates the potency of the compounds against free factor Xa incitrated plasma. For example, the anticoagulant efficacy of thecompounds of the invention will be tested using either the prothrombintime (PT), or activated partial thromboplastin time (aPTT) whileselectivity of the compounds is checked with the thrombin clotting time(TCT) assay. Correlation of the K_(i) in the primary enzyme assay withthe K_(i) for free factor Xa in citrated plasma will screen againstcompounds which interact with or are inactivated by other plasmacomponents. Correlation of the K_(i) with the extension of the PT is anecessary in vitro demonstration that potency in the free factor Xainhibition assay translates into potency in a clinical coagulationassay. In addition, extension of the PT in citrated plasma can be usedto measure duration of action in subsequent pharmacodynamic studies.

For further information on assays to demonstrate the activity of thecompounds of the invention, see R. Lottenberg et al., Methods inEnzymology (1981), Vol. 80, pp. 341-361, and H. Ohno et al., ThrombosisResearch (1980), Vol. 19, pp. 579-588.

C. General Administration

Administration of the compounds of the invention, or theirpharmaceutically acceptable salts, in pure form or in an appropriatepharmaceutical composition, can be carried out via any of the acceptedmodes of administration or agents for serving similar utilities. Thus,administration can be, for example, orally, nasally, parenterally,topically, transdermally, or rectally, in the form of solid, semi-solid,lyophilized powder, or liquid dosage forms, such as for example,tablets, suppositories, pills, soft elastic and hard gelatin capsules,powders, solutions, suspensions, or aerosols, or the like, preferably inunit dosage forms suitable for simple administration of precise dosages.The compositions will include a conventional pharmaceutical carrier orexcipient and a compound of the invention as the/an active agent, and,in addition, may include other medicinal agents, pharmaceutical agents,carriers, adjuvants, etc.

Generally, depending on the intended mode of administration, thepharmaceutically acceptable compositions will contain about 1% to about99% by weight of a compound(s) of the invention, or a pharmaceuticallyacceptable salt thereof, and 99% to 1% by weight of a suitablepharmaceutical excipient. Preferably, the composition will be about 5%to 75% by weight of a compound(s) of the invention, or apharmaceutically acceptable salt thereof, with the rest being suitablepharmaceutical excipients.

The preferred route of administration is oral, using a convenient dailydosage regimen which can be adjusted according to the degree of severityof the disease-state to be treated. For such oral administration, apharmaceutically acceptable composition containing a compound(s) of theinvention, or a pharmaceutically acceptable salt thereof, is formed bythe incorporation of any of the normally employed excipients, such as,for example, pharmaceutical grades of mannitol, lactose, starch,pregelatinized starch, magnesium stearate, sodium saccharine, talcum,cellulose ether derivatives, glucose, gelatin, sucrose, citrate, propylgallate, and the like. Such compositions take the form of solutions,suspensions, tablets, pills, capsules, powders, sustained releaseformulations and the like.

Preferably such compositions will take the form of capsule, caplet ortablet and therefore will also contain a diluent such as lactose,sucrose, dicalcium phosphate, and the like; a disintegrant such ascroscarmellose sodium or derivatives thereof; a lubricant such asmagnesium stearate and the like; and a binder such as a starch, gumacacia, polyvinylpyrrolidone, gelatin, cellulose ether derivatives, andthe like.

The compounds of the invention, or their pharmaceutically acceptablesalts, may also be formulated into a suppository using, for example,about 0.5% to about 50% active ingredient disposed in a carrier thatslowly dissolves within the body, e.g., polyoxyethylene glycols andpolyethylene glycols (PEG), e.g., PEG 1000 (96%) and PEG 4000 (4%).

Liquid pharmaceutically administrable compositions can, for example, beprepared by dissolving, dispersing, etc., a compound(s) of the invention(about 0.5% to about 20%), or a pharmaceutically acceptable saltthereof, and optional pharmaceutical adjuvants in a carrier, such as,for example, water, saline, aqueous dextrose, glycerol, ethanol and thelike, to thereby form a solution or suspension.

If desired, a pharmaceutical composition of the invention may alsocontain minor amounts of auxiliary substances such as wetting oremulsifying agents, pH buffering agents, antioxidants, and the like,such as, for example, citric acid, sorbitan monolaurate, triethanolamineoleate, butylated hydroxytoluene, etc.

Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton,Pa., 1990). The composition to be administered will, in any event,contain a therapeutically effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof, for treatmentof a disease-state alleviated by the inhibition of factor Xa inaccordance with the teachings of this invention.

The compounds of the invention, or their pharmaceutically acceptablesalts, are administered in a therapeutically effective amount which willvary depending upon a variety of factors including the activity of thespecific compound employed, the metabolic stability and length of actionof the compound, the age, body weight, general health, sex, diet, modeand time of administration, rate of excretion, drug combination, theseverity of the particular disease-states, and the host undergoingtherapy. Generally, a therapeutically effective daily dose is from about0.14 mg to about 14.3 mg/kg of body weight per day of a compound of theinvention, or a pharmaceutically acceptable salt thereof; preferably,from about 0.7 mg to about 10 mg/kg of body weight per day; and mostpreferably, from about 1.4 mg to about 7.2 mg/kg of body weight per day.For example, for administration to a 70 kg person, the dosage rangewould be from about 10 mg to about 1.0 gram per day of a compound of theinvention, or a pharmaceutically acceptable salt thereof, preferablyfrom about 50 mg to about 700 mg per day, and most preferably from about100 mg to about 500 mg per day.

Preferred Embodiments

Of the compounds of the invention as set forth above in the Summary ofthe Invention, several groups of compounds are preferred.

One preferred group are those compounds selected from formula (I):##STR4## wherein A is --N═;

Z¹ and Z² are independently --O--, --N(R⁸)-- or --OCH₂ --;

R¹ and R³ are independently hydrogen, fluoro, chloro, haloalkyl,--N(R⁸)R⁹, --C(O)OR⁸, --C(O)N(R⁸)R⁹, --N(R⁸)C(O)N(R⁸)R⁹, --N(R⁸)C(O)R⁸,or --N(R⁸)S(O)₂ R¹² ;

R² is hydrogen; halo; alkyl; haloalkoxy; --OR⁸ ; --C(O)OR⁸ ;--C(O)N(R⁸)R⁹ ; --N(R⁸)R⁹ ; --C(O)N(R⁸)(CH₂)_(m) C(O)OR⁸ (where m is 0to 3); --N(R⁸)(CH₂)_(n) C(O)OR⁸ (where n is 1 to 3); --N((CH₂)_(n)N(R⁸)R⁹)(CH₂)_(n) C(O)OR⁸ (where each n is 1 to 3); --O(CH₂)_(n)C(O)N(R⁸)R⁹ (where n is 1 to 3); --O(CH₂)_(p) C(O)OR⁸ (where p is 1 to6); --N(R⁸)(CH₂)_(n) C(O)N(R⁸)(CH₂)_(n) C(O)OR⁸ (where each n isindependently 1 to 3); morpholin-4-yl; 3-tetrahydrofuranoxy;

or R² is aryloxy (optionally substituted by one or more substituentsindependently selected from the group consisting of --OR⁸,--C(O)N(R⁸)R⁹, halo, alkyl, carboxy, alkoxycarbonyl, haloalkoxy,haloalkoxycarbonyl, alkoxycarbonylalkyl, carboxyalkyl,aminocarbonylalkyl, (alkylamino)carbonylalkyl,(dialkylamino)carbonylalkyl, (arylamino)carbonylalkyl,(aralkylamino)carbonylalkyl, alkoxycarbonylalkenyl, carboxyalkenyl,aminocarbonylalkenyl, (alkylamino)carbonylalkenyl,(dialkylamino)carbonylalkenyl, (arylamino)carbonylalkenyl,(aralkylamino)carbonylalkenyl, (hydroxyalkoxy)carbonyl,(alkoxy)alkoxycarbonyl, (hydroxyalkoxy)alkoxycarbonyl,((alkoxy)alkoxy)alkoxycarbonyl, tetrazolyl, morpholin-4-ylalkyl, and(1,2)-imidazolinyl (optionally substituted by alkyl));

or R² is piperazin-1-yl (optionally substituted by one or moresubstituents independently selected from the group consisting of alkyl,carboxy, --C(O)N(R⁸)R⁹, carboxyalkyl, alkoxycarbonyl, andalkoxycarbonylalkyl);

or R² is 1-piperazinoyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, carboxy,--C(O)N(R⁸)R⁹, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl);

or R² is piperidin-1-yl (optionally substituted by one or moresubstituents selected from the group consisting of carboxy,--C(O)N(R⁸)R⁹, carboxyalkyl, alkoxycarbonyl, or alkoxycarbonylalkyl);

or R² is (3,4)-piperidinyloxy (optionally substituted by one or moresubstituents selected from the group consisting of alkylcarbonyl,carboxy, --C(O)N(R⁸)R⁹, alkoxycarbonyl, carboxyalkyl,alkoxycarbonylalkyl, or tetrazolylalkyl);

or R² is piperidin-4-ylamino (wherein the amino is optionallysubstituted by alkyl and the piperidinyl group is optionally substitutedby one or more substituents selected from the group consisting of alkyl,alkoxycarbonyl, carboxyalkyl, --C(O)N(R⁸)R⁹, alkoxycarbonylalkyl oraralklyl);

or R² is 3-pyrrolidinyloxy (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aralkyl,amidino, 1-iminoethyl, carboxy, carboxyalkyl, alkoxycarbonyl,--C(O)N(R⁸)R⁹, or alkoxycarbonylalkyl);

R⁴ is hydrogen, --OR⁸ or --N(R⁸)R⁹ ;

R⁵ is --C(NH)NH₂ ;

R⁶ is guanidino, --C(NH)NH₂, --C(O)N(R⁸)R⁹, --CH(OH)C(O)N(R⁸)R⁹,--(CH₂)_(m) N(R⁸)R⁹ (where m is 0 to 3), 1-piperidinoyl,1-pyrrolidinoyl, (1,2)-imidazolyl (optionally substituted by alkyl), or(1,2)-imidazolinyl (optionally substituted by alkyl);

R⁷ is hydrogen, halo, alkyl, --OR⁸, --C(O)N(R⁸)R9;

R⁸ and R⁹ are independently hydrogen, methyl, ethyl or phenyl; and

R¹² is methyl, ethyl, phenyl or benzyl.

Of this group of compounds, a preferred subgroup of compounds is thatsubgroup wherein

Z¹ and Z² are independently --O-- or --NCH₃ --;

R¹ and R³ are independently hydrogen, fluoro, chloro, trifluoromethyl,amino, --C(O)N(R⁸)R⁹, or --NHC(O)NHR⁹ ;

R² is hydrogen; alkyl; haloalkoxy; --OR⁸ ; --C(O)OR⁸ ; --N(R⁸)R⁹ ;--N(R⁸)(CH₂)_(n) C(O)OR⁸ (where n is 1 to 3); --N((CH₂)_(n)N(R⁸)R⁹)(CH₂)_(n) C(O)OR⁸ (where each n is 1 to 3); --O(CH₂)_(n)C(O)N(R⁸)R⁹ (where n is 1 to 3); --O(CH₂)_(p) C(O)OR⁸ (where p is 1 to6); --N(R⁸)(CH₂)_(n) C(O)N(R⁸)(CH₂)_(n) C(O)OR⁸ (where each n isindependently 1 to 3); morpholin-4-yl; 3-tetrahydrofuranoxy;

or R² is aryloxy (optionally substituted by one or more substituentsindependently selected from the group consisting of --OR⁸,--C(O)N(R⁸)R⁹, halo, alkyl, carboxy, alkoxycarbonyl,alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonylalkenyl,carboxyalkenyl, tetrazolyl, morpholin-4-ylalkyl, and (1,2)-imidazolinyl(optionally substituted by alkyl));

or R² is piperazin-1-yl (optionally substituted by one or moresubstituents independently selected from the group consisting of alkyl,carboxyalkyl, and alkoxycarbonylalkyl);

or R² is piperidin-1-yl (optionally substituted by one or moresubstituents selected from the group consisting of carboxy andalkoxycarbonyl);

or R² is (3,4)-piperidinyloxy (optionally substituted by one or moresubstituents selected from the group consisting of carboxyalkyl andalkoxycarbonylalkyl);

or R² is piperidin-4-ylamino (wherein the amino is optionallysubstituted by alkyl and the piperidinyl group is optionally substitutedby one or more substituents selected from the group consisting ofcarboxyalkyl, alkoxycarbonylalkyl and aralklyl);

or R² is 3-pyrrolidinyloxy (optionally substituted by one or moresubstituents selected from the group consisting of 1-iminoethyl,carboxy, carboxyalkyl, alkoxycarbonyl and alkoxycarbonylalkyl);

R⁴ is hydrogen, amino, hydroxy, or methoxy;

R⁵ is --C(NH)NH₂ ;

R⁶ is guanidino, --C(NH)NH₂, --C(O)N(R⁸)R⁹, --(CH₂)_(m) N(R⁸)R⁹ (where mis 0 to 1), (1,2)-imidazolyl substituted by alkyl, or 2-imidazolinylsubstituted by alkyl;

R⁷ is hydrogen, methoxy, or hydroxy; and

R⁸ and R⁹ are independently hydrogen, methyl, ethyl, or phenyl.

Of this subgroup of compounds, a preferred class of compounds is thatclass wherein Z¹ and Z² are both --O--; R¹ and R³ are independentlyhydrogen, fluoro, or chloro; R⁴ is amino, hydrogen, hydroxy or methoxy;R⁶ is guanidino, --C(NH)NH₂, --C(O)N(R⁸)R⁹, --(CH₂)_(m) N(R⁸)R⁹ (where mis 0 or 1), (1,2)-imidazolyl substituted by methyl, or 2-imidazolinyloptionally substituted by methyl; and R⁷ is hydrogen or hydroxy.

Of this class of compounds, a preferred subclass of compounds is thatsubclass wherein R⁴ is hydroxy; R⁶ is dimethylamino ordimethylaminocarbonyl; and R⁷ is hydrogen.

Of this subclass of compounds, preferred compounds are selected from thefollowing:

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-ethoxycarbonylmethylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-propoxypyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-carboxypiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-dimethylaminopyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1,3-difluoroprop-2-oxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-bromo-3-fluoroprop-2-oxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-((methyl)(carboxymethyl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-methoxy-pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(3-carboxypiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-carboxymethylpiperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(piperidin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-methylpiperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(morpholin-4-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(4-carboxymethylpiperazinyl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(4-ethoxycarbonylmethylpiperazinyl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(4-carboxy-2-methoxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(4-carboxy-2-(morpholin-4-ylmethyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-((methyl)(carboxymethyl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(aminocarbonylmethoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(1-carboxymethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-carboxymethoxypyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-((2-dimethylaminoethyl)(carboxymethyl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(1-(1-iminoethyl)pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(pyrrolidin-3-yloxy)pyridin-2-yl]oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-ethoxycarbonylmethylpyrrolidin-3-yloxy)pyridin-2-yl]oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-(1-iminoethyl)pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-((1-carboxymethyl)pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;and

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-((methyl)((carboxymethyl)aminocarbonylmethyl)amino)pyridin-2-yl)oxy]benzamidine.

Of this class of compounds, another preferred subclass of compounds isthat subclass wherein wherein R⁴ is hydroxy; R⁶ is (1,2)-imidazolylsubstituted by methyl or 2-imidazolinyl substituted by methyl; and R⁷ ishydrogen.

Of this subclass, preferred compounds are selected from the following:

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((methyl)(carboxymethyl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((methyl)(ethoxycarbonylmethyl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-(1-(methoxycarbonyl)ethyl)piperidin-4-yl)aminopyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethoxy-4-(2-(ethoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethoxy-4-(2-carboxyethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(5-carboxypyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-(1-(ethoxycarbonyl)ethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-hydroxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-5-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,3-dimethoxy-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,3-dimethoxy-5-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-aminocarbonyl-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-(1-methylimidazolin-2-yl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethoxy-4-methoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethoxy-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3,5-dicarboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-4-(3-(1-methylimidazolin-2-yl)phenoxy)-6-(3,5-dicarboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-carboxy-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethoxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-hydroxy-4-methoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-amidinophenoxy)-4-(2-methoxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-aminocarbonyl-5-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-chloro-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethyl-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-ethoxycarbonylmethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-(ethoxycarbonylmethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(5-ethoxycarbonylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-carboxymethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-(1-carboxy-1-methylethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-ethoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-ethoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-carboxypiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-carboxypiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-(2-ethoxycarbonylethyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-ethoxycarbonylmethylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-carboxymethylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-5-(tetrazol-5-yl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-((2-dimethylaminoethyl)(carboxymethyl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-carboxymethylpiperidin-4-yl)(methyl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-carboxymethylpiperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-ethoxycarbonylmethylpiperidin-4-yl)(methyl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-(ethoxycarbonylmethyl)piperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((piperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-benzylpiperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((piperidin-4-yl)(methyl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-benzylpiperidin-4-yl)(methyl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(5-carboxypent-1-oxy)pyridin-2-yl)oxy]benzamidine;and

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-carboxymethylpiperazin-1-yl)pyridin-2-yl)oxy]benzamidine.

Of this class of compound, another preferred subclass of compounds isthat subclass wherein R⁴ is hydroxy; R⁶ is guanidino; and R⁷ ishydrogen.

Of this subclass of compounds, preferred compounds are selected from thefollowing:

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-((1-ethoxycarbonylmethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(1-carboxymethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(5-ethoxycarbonylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2,6-dimethoxy-4-methoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-guanidino)phenoxy)-4-(2,6-dimethoxy-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2,6-dimethoxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2,6-dimethoxy-4-aminocarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

-4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(methyl)(phenyl)aminocarbonylpyridin-2-yl)oxy]benzamidine;and

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(4-carboxymethylpiperazin-1-yl)pyridin-2-yl)oxy]benzamidine.

Another preferred group of compounds are selected from formula (VII):##STR5## wherein Z¹ and Z² are independently --O--, --N(R⁸)-- or --OCH₂--;

R¹ and R³ are independently hydrogen, fluoro, chloro, haloalkyl,--N(R⁸)R⁹, --C(O)OR⁸, --C(O)N(R⁸)R⁹, --N(R⁸)C(O)N(R⁸)R⁹, --N(R⁸)C(O)R⁸,or --N(R⁸)S(O)₂ R¹² ;

R² is hydrogen; halo; alkyl; haloalkoxy; --OR⁸ ; --C(O)OR⁸ ;--C(O)N(R⁸)R⁹ ; --N(R⁸)R⁹ ; --C(O)N(R⁸)(CH₂)_(m) C(O)OR⁸ (where m is 0to 3); --N(R⁸)(CH₂)_(n) C(O)OR⁸ (where n is 1 to 3); --N((CH₂)_(n)N(R⁸)R⁹)(CH₂)_(n) C(O)OR⁸ (where each n is 1 to 3); --O(CH₂)_(n)C(O)N(R⁸)R⁹ (where n is 1 to 3); --O(CH₂)_(p) C(O)OR⁸ (where p is 1 to6); --N(R⁸)(CH₂)_(n) C(O)N(R⁸)(CH₂)_(n) C(O)OR⁸ (where each n isindependently 1 to 3); morpholin-4yl; 3-tetrahydrofuranoxy;

or R² is aryloxy (optionally substituted by one or more substituentsindependently selected from the group consisting of --OR⁸,--C(O)N(R⁸)R⁹, halo, alkyl, carboxy, alkoxycarbonyl, haloalkoxy,haloalkoxycarbonyl, alkoxycarbonylalkyl, carboxyalkyl,aminocarbonylalkyl, (alkylamino)carbonylalkyl,(dialkylamino)carbonylalkyl, (arylamino)carbonylalkyl,(aralkylamino)carbonylalkyl, alkoxycarbonylalkenyl, carboxyalkenyl,aminocarbonylalkenyl, (alkylamino)carbonylalkenyl,(dialkylamino)carbonylalkenyl, (arylamino)carbonylalkenyl,(aralkylamino)carbonylalkenyl, (hydroxyalkoxy)carbonyl,(alkoxy)alkoxycarbonyl, (hydroxyalkoxy)alkoxycarbonyl,((alkoxy)alkoxy)alkoxycarbonyl, tetrazolyl, morpholin-4-ylalkyl, and(1,2)-imidazolinyl (optionally substituted by alkyl));

or R² is piperazin-1-yl (optionally substituted by one or moresubstituents independently selected from the group consisting of alkyl,carboxy, --C(O)N(R⁸)R⁹, carboxyalkyl, alkoxycarbonyl, andalkoxycarbonylalkyl);

or R² is 1-piperazinoyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, carboxy,--C(O)N(R⁸)R⁹, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl);

or R² is piperidin-1-yl (optionally substituted by one or moresubstituents selected from the group consisting of carboxy,--C(O)N(R⁸)R⁹, carboxyalkyl, alkoxycarbonyl, or alkoxycarbonylalkyl);

or R² is (3,4)-piperidinyloxy (optionally substituted by one or moresubstituents selected from the group consisting of alkylcarbonyl,carboxy, --C(O)N(R⁸)R⁹, alkoxycarbonyl, carboxyalkyl,alkoxycarbonylalkyl, or tetrazolylalkyl);

or R² is piperidin-4-ylamino (wherein the amino is optionallysubstituted by alkyl and the piperidinyl group is optionally substitutedby one or more substituents selected from the group consisting of alkyl,alkoxycarbonyl, carboxyalkyl, --C(O)N(R⁸)R⁹, alkoxycarbonylalkyl oraralklyl);

or R² is 3-pyrrolidinyloxy (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aralkyl,amidino, 1-iminoethyl, carboxy, carboxyalkyl, --C(O)N(R⁸)R⁹,alkoxycarbonyl or alkoxycarbonylalkyl);

R⁴ is hydrogen, --OR⁸ or --N(R⁸)R⁹ ;

R⁵ is --C(NH)NH₂ ;

R⁶ is guanidino, --C(NH)NH₂, --C(O)N(R⁸)R⁹, --CH(OH)C(O)N(R⁸)R⁹,--(CH₂)_(m) N(R⁸)R⁹ (where m is 0 to 3), 1-piperidinoyl,1-pyrrolidinoyl, (1,2)-imidazolyl (optionally substituted by alkyl), or(1,2)-imidazolinyl (optionally substituted by alkyl);

R⁷ is hydrogen, halo, alkyl, --OR⁸, --C(O)N(R⁸)R⁹ ;

R⁸ and R⁹ are independently hydrogen, methyl, ethyl or phenyl;

R¹² is methyl, ethyl, phenyl or benzyl.

Of this group of compounds, a preferred subgroup of compounds is thatsubgroup wherein Z¹ and Z² are independently --O-- or --NCH₃ --;

R¹ and R³ are independently hydrogen, fluoro, chloro, trifluoromethyl,amino, --C(O)N(R⁸)R⁹, or --NHC(O)NHR⁹ ;

R² is hydrogen; alkyl; haloalkoxy; --OR⁸ ; --C(O)OR⁸ ; --N(R⁸)R⁹ ;--N(R⁸)(CH₂)_(n) C(O)OR⁸ (where n is 1 to 3); --N((CH₂)_(n)N(R⁸)R⁹)(CH₂)_(n) C(O)OR⁸ where each n is 1 to 3); --O(CH₂)_(n)C(O)N(R⁸)R⁹ (where n is 1 to 3); --O(CH₂)_(p) C(O)OR⁸ (where p is 1 to6); --N(R⁸)(CH₂)_(n) C(O)N(R⁸)(CH₂)_(n) C(O)OR⁸ (where each n isindependently 1 to 3); morpholin-4-yl; 3-tetrahydrofuranoxy;

or R² is aryloxy (optionally substituted by one or more substituentsindependently selected from the group consisting of --OR⁸,--C(O)N(R⁸)R⁹, halo, alkyl, carboxy, alkoxycarbonyl,alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonylalkenyl,carboxyalkenyl, tetrazolyl, morpholin-4-ylalkyl, and (1,2)-imidazolinyl(optionally substituted by alkyl));

or R² is piperazin-1-yl (optionally substituted by one or moresubstituents independently selected from the group consisting of alkyl,carboxyalkyl, and alkoxycarbonylalkyl);

or R² is piperidin-1-yl (optionally substituted by one or moresubstituents selected from the group consisting of carboxy andalkoxycarbonyl);

or R² is (3,4)-piperidinyloxy (optionally substituted by one or moresubstituents selected from the group consisting of carboxyalkyl andalkoxycarbonylalkyl);

or R² is piperidin-4-ylamino (wherein the amino is optionallysubstituted by alkyl and the piperidinyl group is optionally substitutedby one or more substituents selected from the group consisting ofcarboxyalkyl, alkoxycarbonylalkyl and aralklyl);

or R² is 3-pyrrolidinyloxy (optionally substituted by one or moresubstituents selected from the group consisting of 1-iminoethyl,carboxy, carboxyalkyl, alkoxycarbonyl and alkoxycarbonylalkyl);

R⁴ is hydrogen, amino, hydroxy, or methoxy;

R⁵ is --C(NH)NH₂ ;

R⁶ is guanidino, --C(NH)NH₂, --C(O)N(R⁸)R⁹, --(CH₂)_(m) N(R⁸)R⁹ (where mis 0 to 1), (1,2)-imidazolyl substituted by alkyl, or 2-imidazolinylsubstituted by alkyl;

R⁷ is hydrogen, methoxy, or hydroxy; and

R⁸ and R⁹ are independently hydrogen, methyl, ethyl, or phenyl.

Of this subgroup of compounds, a preferred class of compounds is thatclass wherein Z¹ and Z² are both --O--; R¹ and R³ are independentlyhydrogen, fluoro, or chloro; R⁴ is amino, hydrogen, hydroxy or methoxy;R⁶ is guanidino, --C(NH)NH₂, --C(O)N(R⁸)R⁹, --(CH₂)_(m) N(R⁸)R⁹ (where mis 0 or 1), (1,2)-imidazolyl substituted by methyl, or 2-imidazolinyloptionally substituted by methyl; and R⁷ is hydrogen or hydroxy.

Of this class of compounds, a preferred subclass of compounds is thatsubclass wherein R⁴ is hydroxy; R⁶ is dimethylamino ordimethylaminocarbonyl; and R⁷ is hydrogen.

Of this subclass of compounds, preferred compounds are4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxyl-2-methoxypyridin-4-yl)oxy]benzamidine;and

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonyl-phenoxy)-2-(2-methoxy-5-ethoxycarbonylphenoxy)pyridin-4-yl)oxy]benzamidine.

PREPARATION OF COMPOUNDS OF THE INVENTION

As a matter of convenience, the following description of thepreparation-of the compounds of the invention is directed to thepreparation of compounds of formula (I). It is understood, however, thatsimilar synthetic processes may be used to prepare the compounds offormula (II), (III), (IV), (V), (VI), (VII) and (VIII). It is alsounderstood that in the following description, combinations ofsubstituents and/or variables (e.g., R⁴ and R⁵) on the depicted formulaeare permissible only if such combinations result in stable compounds.

A. Preparation of Intermediates

1. Compounds of Formula (C)

Compounds of formula (C), as shown below, are intermediates in thepreparation of the compounds of the invention. As illustrated below inReaction Scheme 1, compounds of formula (C) are prepared from compoundsof formulae (A) and (B) wherein X is chloro or fluoro and R^(2a) is--N(R⁸)R⁹, --N(R⁸)(CH₂)_(m) C(O)OR⁸ (where m is 0 to 3) or piperazinyl(optionally substituted by alkyl, carboxy, carboxyalkyl, alkoxycarbonylor alkoxycarbonylalkyl); and each R⁸ and R⁹ is independently hydrogen,alkyl, aryl or aralkyl: ##STR6##

Compounds of formula (A) and (B) can be prepared according to methodsknown to those of ordinary skill in the art or are commerciallyavailable, for example, from Aldrich Chemical Company, Inc. or fromMaybridge Co.

In general, compounds of formula (C) are prepared by reacting a compoundof formula (A) with an equimolar amount of a compound of formula (B) at0° C. to 40° C., preferably at ambient temperature, in the presence of abase, e.g., triethylamine, or in the presence of a second equivalent ofthe compounds of formula (B). The compounds of formula (C) are isolatedfrom the resulting reaction mixture by conventional methods.

2. Compounds of Formula (F)

Compounds of formula (F), as shown below, are also intermediates in thepreparation of the compounds of the invention. As illustrated below inReaction Scheme 2, compounds of formula (F) are prepared from compoundsof formulae (D) and (E) where each X is independently chloro or fluoro;and R² is alkoxy, haloalkoxy, --O(CH)_(p) C(O)OR⁸ (where p is 1 to 6),--N(R⁸)R⁹, --N(R⁸)(CH₂)_(n) C(O)OR⁸ (where n is 1 to 3),--N(R⁸)(CH₂)_(n) C(O)N(R⁸)(CH₂)_(n) C(O)OR⁸ (where each n isindependently 1 to 3), morpholin-4-yl, 3-tetrahydrofuranyloxy; or R² isaryloxy (optionally substituted by one or more substituentsindependently selected from the group consisting of --OR⁸,--C(O)N(R⁸)R⁹, halo, alkyl, alkoxycarbonyl, haloalkoxy,haloalkoxycarbonyl, alkoxycarbonylalkyl, aminocarbonylalkyl,(alkylamino)carbonylalkyl, (dialkylamino)carbonylalkyl,(arylamino)carbonylalkyl, (aralkylamino)carbonylalkyl,alkoxycarbonylalkenyl, aminocarbonylalkenyl,(alkylamino)carbonylalkenyl, (dialkylamino)carbonylalkenyl,(arylamino)carbonylalkenyl, (aralkylamino)carbonylalkenyl,(hydroxyalkoxy)carbonyl, (alkoxy)alkoxycarbonyl,(hydroxyalkoxy)alkoxycarbonyl, ((alkoxy)alkoxy)alkoxycarbonyl,tetrazolyl, morpholin-4-ylalkyl, and (1,2)-imidazolinyl (optionallysubstituted by alkyl)); or R² is 1-piperidinyl (optionally substitutedby alkoxycarbonyl or alkoxycarbonylalkyl); or R² is 1-piperazinyl(optionally substituted by alkyl, alkoxycarbonyl oralkoxycarbonylalkyl); or R² is (3,4)-piperidinyloxy (optionallysubstituted by alkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl ortetrazolylalkyl); or R² is piperidin-4-ylamino (wherein the amino isoptionally substituted by alkyl and the piperidinyl group is optionallysubstituted by alkyl, alkoxycarbonyl, alkoxycarbonylalkyl or aralklyl);or R² is 3-pyrrolidinyloxy (optionally substituted by alkyl, aralkyl oralkoxycarbonylalkyl); and each R⁸ and R⁹ is independently hydrogen,alkyl, aryl or aralkyl: ##STR7##

Compounds of formulae (D) and (E) are commercially available, forexample, from Aldrich Chemical Company, Inc., or may be preparedaccording to methods known to those skilled in the art.

In general, compounds of formula (F) are prepared by treating a compoundof formula (D) with a compound of formula (E) in an aprotic solvent, forexample, methylene chloride, at between about 0° C. and 50° C.,preferably at ambient temperature, and, if the hydrogen in the compoundof formula (E) is an hydroxyl hydrogen, in the presence of a base, forexample, cesium carbonate. The compound of formula (F) is isolated fromthe reaction mixture by standard techniques.

3. Compounds of Formulae (J) and (K)

Compounds of formulae (J) and (K), as shown below, are alsointermediates in the preparation of the compounds of the invention. Asillustrated below in Reaction Scheme 3, compounds of formula (J) and (K)are prepared from compounds of formula (G) and formula (H) where A is--N═ or --C(R¹¹)═ (where R¹¹ is hydrogen, alkyl or halo); X is fluoro ofchloro; R¹ and R³ are independently hydrogen, halo, alkyl, haloalkyl,alkoxy, haloalkoxy, nitro, --N(R⁸)R⁹, --C(O)OR⁸, --C(O)N(R⁸)R⁹,--C(O)N(R⁸)CH₂ C(O)N(R⁸)R⁹, --N(R⁸)C(O)N(R⁸)R⁹, --N(R⁸)C(O)R⁸,--N(R⁸)S(O)₂ R¹², or --N(R⁸)C(O)N(R⁸)CH₂ --C(O)N(R⁸)R⁹ ; R² is hydrogen,alkyl, haloalkoxy, --OR¹², --C(O)OR⁸, --C(O)N(R⁸)R⁹, --N(R⁸)R⁹,--C(O)N(R⁸)(CH₂)_(n) C(O)OR⁸ (where m is 0 to 3), --N(R⁸)(CH₂)_(n)C(O)OR⁸ (where n id 1 to 3), --N((CH₂)_(n) N(R⁸)R⁹)(CH₂)_(n) C(O)OR⁸(where each n is 1 to 3), --O(CH₂)_(n) C(O)N(R⁸)R⁹ (where n is 1 to 3),--O(CH₂)_(p) C(O)OR⁸ (where p is 1 to 6), --N(R⁸)(CH₂)_(n)C(O)N(R⁸)(CH₂)_(n) C(O)OR⁸ (where each n is independently 1 to 3),morpholin-4-yl, 3-tetrahydrofuranoxy; or R² is aryloxy (optionallysubstituted by one or more substituents independently selected from thegroup consisting of --OR¹², --C(O)N(R⁸)R⁹, halo, alkyl, alkoxycarbonyl,haloalkoxy, haloalkoxycarbonyl, alkoxycarbonylalkyl, aminocarbonylalkyl,(alkylamino)carbonylalkyl, (dialkylamino)carbonylalkyl,(arylamino)carbonylalkyl, (aralkylamino)carbonylalkyl,alkoxycarbonylalkenyl, aminocarbonylalkenyl,(alkylamino)carbonylalkenyl, (dialkylamino)carbonylalkenyl,(arylamino)carbonylalkenyl, (aralkylamino)carbonylalkenyl,(hydroxyalkoxy)carbonyl, (alkoxy)alkoxycarbonyl,(hydroxyalkoxy)alkoxycarbonyl, ((alkoxy)alkoxy)alkoxycarbonyl,tetrazolyl, morpholin-4-ylalkyl, and (1,2)-imidazolinyl (optionallysubstituted by alkyl)); or R² is piperazin-1-yl (optionally substitutedby one or more substituents independently selected from the groupconsisting of alkyl, alkoxycarbonyl, and alkoxycarbonylalkyl); or R² is1-piperazinoyl (opt onally substituted by one or more substituentsselected from the group consisting of alkyl, alkoxycarbonyl, andalkoxycarbonylalkyl); or R² is piperidin-1-yl (optionally substituted byone or more substituents selected from the group consisting ofalkoxycarbonyl, and alkoxycarbonylalkyl); or R² is (3,4)-piperidinyloxy(optionally substituted by one or more substituents selected from thegroup consisting of alkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl,and tetrazolylalkyl); or R² is piperidin-4-ylamino (wherein the amino isoptionally substituted by alkyl and the piperidinyl group is optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, alkoxycarbonyl, alkoxycarbonylalkyl and aralklyl);or R² is 3-pyrrolidinyloxy (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aralkyl,alkoxycarbonyl and alkoxycarbonylalkyl); R⁴ is independently hydrogen,halo, alkyl, nitro, --OR¹², --C(O)OR⁸, --C(O)N(R⁸)R⁹, --N(R⁸)R⁹, or--N(H)C(O)R⁸ ; each R⁸ and R⁹ is independently hydrogen, alkyl, aryl oraralkyl; and R¹² is alkyl, aryl or aralkyl: ##STR8##

Compounds of formula (G) include compounds of formulae (C) and (F) asdescribed above, or may be prepared by methods described herein or bymethods known to one of ordinary skill in the art. They may also becommercially available, for example, from Aldrich Chemical Co., Inc. orfrom Maybridge Co. Compounds of formula (H) may be prepared by methodsknown to one of ordinary skill in the art or may be commerciallyavailable, for example, from Aldrich Chemical Co., Inc.

In general, the compounds of formulae (J) and (K) are prepared byreacting a compound of formula (G) with a compound of formula (H) (in anequimolar amount for a compound of formula (K) and with two or moreequivalents of a compound of formula (H) for a compound of formula (J))in the presence of a base, e.g., sodium hydride or cesium carbonate, attemperatures between about 20° C. and 120° C., preferably, for compoundsof formula (J), at temperatures of around 50° C., in an aprotic solvent,for example, dimethylformamide, DMSO or acetonitrile, for a period oftime sufficient to complete the desired reaction as monitored by thinlayer chromatography (TLC). Compounds of formulae (J) and (K) are thenisolated from the reaction mixture by standard isolation techniques.

In a similar manner, compounds of formula (G) may be treated withcompounds of formula (H) wherein the hydroxy group is replaced by anamino group to produce compounds of formulae (J) and (K) wherein theether connecting group is replaced by an amino connecting group. Theamino group can then be alkylated by standard procedures.

Compounds of formulae (J) and (K) wherein R⁴ is an amino group may befurther treated with an alkylsulfonyl halide, e.g.,methylsulfonylchloride, under basic conditions at ambient temperature toproduce compounds of formulae (J) and (K) wherein R⁴ is --N(H)S(O)₂ R¹².

4. Compounds of Formula (M)

Compounds of formula (M), as shown below, are also intermediates in thepreparation of the compounds of the invention. As illustrated below inReaction Scheme 4, compounds of formula (M) are prepared from compoundsof formula (K) and formula (L) where A is --N═ or --C(R¹¹)═ (where R¹¹is hydrogen, alkyl or halo); X is fluoro of chloro; R¹ and R³ areindependently hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy,nitro, --N(R⁸)R⁹, --C(O)OR⁸, --C(O)N(R⁸)R⁹, --C(O)N(R⁸)CH₂ C(O)N(R⁸)R⁹,or --N(R⁸)C(O)N(R⁸)CH₂ C(O)N(R⁸)R⁹ ; R² is hydrogen, alkyl, haloalkoxy,--OR¹², --C(O)OR⁸, --C(O)N(R⁸)R⁹, --N(R⁸)R⁹, --C(O)N(R⁸)(CH₂)_(m)C(O)OR⁸ (where m is 0 to 3), --N(R⁸)(CH₂)_(n) C(O)N(R⁸)R⁹ (where n is 1to 3), --N((CH₂)_(n) N(R⁸)R⁹)(CH₂)_(n) C(O)OR⁸ (where each n is 1 to 3),--O(CH₂)_(n) C(O)N(R⁸)R⁹ (where n is 1 to 3), --O(CH₂)_(p) C(O)OR⁸(where p is 1 to 6), --N(R⁸)(CH₂)_(n) C(O)N(R⁸)(CH₂)_(n) C(O)OR⁸ (whereeach n is independently 1 to 3), morpholin-4-yl, 3-tetrahydrofuranoxy;or R² is aryloxy (optionally substituted by one or more substituentsindependently selected from the group consisting of --OR¹²,--C(O)N(R⁸)R⁹, halo, alkyl, alkoxycarbonyl, haloalkoxy,haloalkoxycarbonyl, alkoxycarbonylalkyl, aminocarbonylalkyl,(alkylamino)carbonylalkyl, (dialkylamino)carbonylalkyl,(arylamino)carbonylalkyl, (aralkylamino)carbonylalkyl,alkoxycarbonylalkenyl, aminocarbonylalkenyl,(alkylamino)carbonylalkenyl, (dialkylamino)carbonylalkenyl,(arylamino)carbonylalkenyl, (aralkylamino)carbonylalkenyl,(hydroxyalkoxy)carbonyl, (alkoxy)alkoxycarbonyl,(hydroxyalkoxy)alkoxycarbonyl, ((alkoxy)alkoxy)alkoxycarbonyl,tetrazolyl, morpholin-4-ylalkyl, and (1,2)-imidazolinyl (optionallysubstituted by alkyl)); or R² is piperazin-1-yl (optionally substitutedby one or more substituents independently selected from the groupconsisting of alkyl, alkoxycarbonyl, and alkoxycarbonylalkyl); or R² is1-piperazinoyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, alkoxycarbonyl, andalkoxycarbonylalkyl); or R² is piperidin-1-yl (optionally substituted byone or more substituents selected from the group consisting ofalkoxycarbonyl, and alkoxycarbonylalkyl); or R² is (3,4)-piperidinyloxy(optionally substituted by one or more substituents selected from thegroup consisting of alkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl,and tetrazolylalkyl); or R² is piperidin-4-ylamino (wherein the amino isoptionally substituted by alkyl and the piperidinyl group is optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, alkoxycarbonyl, alkoxycarbonylalkyl and aralklyl);or R² is 3-pyrrolidinyloxy (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aralkyl,alkoxycarbonyl and alkoxycarbonylalkyl); R⁴ and R⁷ are independentlyhydrogen, halo, alkyl, nitro, --OR¹², --C(O)OR⁸, --C(O)N(R⁸)R⁹,--N(R⁸)R⁹, or --N(H)C(O)R⁸ ; R⁶ is halo, alkyl, haloalkyl, haloalkoxy,nitro, amino, ureido, guanidino, --OR¹², --C(NH)NH₂, --C(NH)NHOH,--C(O)R¹⁰, --(CH₂)_(m) C(O)N(R⁸)R⁹ (where m is 0 to 3),--CH(OH)C(O)N(R⁸)R⁹, --(CH₂)_(m) N(R⁸)R⁹ (where m is 0 to 3),--(CH₂)_(m) C(O)OR⁸ (where m is 0 to 3), --N(H)C(O)R⁸,(1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl),(1,2)-imidazolyl (optionally substituted by alkyl), or(1,2)-imidazolinyl (optionally substituted by alkyl); each R⁸ and R⁹ isindependently hydrogen, alkyl, aryl, or aralkyl; and R¹² is alkyl, arylor aralkyl: ##STR9##

Compounds of formula (K) are prepared according to the methods describedherein (see Reaction Scheme 3 above). Compounds of formula (L) arecommercially available, for example, from Aldrich Chemical Co., or fromMaybridge Co., or may be prepared according to methods known to those ofordinary skill in the art.

In general, the compounds of formula (M) are prepared in a mannersimilar to that described above for compounds of formula (J) and (K).

Compounds of formula (M) where R⁴ or R⁷ is hydroxy may be reacted with ahaloalkane, such as iodomethane, under standard conditions to producethe corresponding compounds of formula (M) where R⁴ or R⁷ is alkoxy.

Compounds of formula (M) where R⁶ or R⁷ contains --C(O)OR⁸ where R⁸ isalkyl or aryl may be hydrolyzed under basic conditions (for example, inthe presence of sodium hydroxide) to produce compounds of formula (M)where R⁶ or R⁷ contains --C(O)OR⁸ where R⁸ is hydrogen.

Compounds of formula (M) where the ether connecting group has beenreplaced by an unsubstituted amino connecting group may be treated withan alkylating agent, such as iodomethane, in the presence of a base, toproduce compounds of formula (M) wherein the amino connecting group issubstituted by alkyl, aryl, or aralkyl. In addition, compounds offormula (K) can be treated with a compound of formula (L) wherein thehydroxy group is replaced by a hydroxymethyl (--CH₂ OH) group to producethe corresponding compounds of formula (M).

Compounds of formula (M) where each R⁶ and R⁷ independently contains--C(O)OR⁸ where R⁸ is hydrogen may be amidated or esterified understandard conditions to produce compounds of formula (M) where R⁶ or R⁷contains --C(O)OR⁸ where R⁸ is alkyl, aryl or aralkyl, or compounds offormula (M) where R⁶ or R⁷ contains --C(O)N(R⁸)R⁹ where R⁸ and R⁹ areindependently hydrogen, alkyl, aryl or aralkyl.

Compounds of formula (M) where R³ is nitro may be reduced under standardconditions to produce compounds of formula (M) where R³ is amino; whichcan then be reacted with the appropriate acid halide or aryl- oralkylsulfonyl halide to produce compounds of formula (M) where R³ is--N(R⁸)C(O)R⁸ or --N(R⁸)S(O)₂ R¹² where R⁸ and R¹² are as defined above.In addition, compounds of formula (M) where R³ is amino can be reactedwith an isocyanate or chloroformate to produce compounds of formula (M)where R³ is --N(R⁸)C(O)N(R⁸)R⁹ or --N(R⁸)C(O)OR⁸.

5. Compounds of Formula (P)

Compounds of formula (P), as shown below, are also intermediates in thepreparation of the compounds of the invention, particularly thosecompounds of formula (I) wherein A is --C(R¹¹)═. As illustrated below inReaction Scheme 5, compounds of formula (P) are prepared from compoundsof formulae (N) and (O) where X is fluoro or chloro; R¹ and R³ areindependently hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy,--N(R⁸)R⁹, --C(O)OR⁸, --C(O)N(R⁸)R⁹, --C(O)N(R⁸)CH₂ C(O)N(R⁸)R⁹,--N(R⁸)C(O)N(R⁸)R⁹, --N(R⁸)C(O)R⁸, --N(R⁸)S(O)₂ R¹², or--N(R⁸)C(O)N(R⁸)CH₂ --C(O)N(R⁸)R⁹ ; R² is hydrogen, alkyl, haloalkoxy,--OR¹², --C(O)OR⁸, --C(O)N(R⁸)R⁹, --N(R⁸)R⁹, --C(O)N(R⁸)(CH₂)_(m)C(O)OR⁸ (where m is 0 to 3), --N(R⁸)(CH₂)_(n) C(O)OR⁸ (where n is 1 to3), --N((CH₂)_(n) N(R⁸)R⁹)(CH₂)_(n) C(O)OR⁸ (where each n is 1 to 3),--O(CH₂)_(n) C(O)N(R⁸)R⁹ (where n is 1 to 3), --O(CH₂)_(p) C(O)OR⁸(where p is 1 to 6), --N(R⁸)(CH₂)_(n) C(O)N(R⁸)(CH₂)_(n) C(O)OR⁸ (whereeach n is independently 1 to 3), morpholin-4-yl, 3-tetrahydrofuranoxy;or R² is aryloxy (optionally substituted by one or more substituentsindependently selected from the group consisting of --OR¹²,--C(O)N(R⁸)R⁹, halo, alkyl, carboxy, alkoxycarbonyl, haloalkoxy,haloalkoxycarbonyl, alkoxycarbonylalkyl, carboxyalkyl,aminocarbonylalkyl, (alkylamino)carbonylalkyl,(dialkylamin,)carbonylalkyl, (arylamino)carbonylalkyl,(aralkylamino)carbonylalkyl, alkoxycarbonylalkenyl, carboxyalkenyl,aminocarbonylalkenyl, (alkylamino)carbonylalkenyl,(dialkylamino)carbonylalkenyl, (arylamino)carbonylalkenyl,(aralkylamino)carbonylalkenyl, (hydroxyalkoxy)carbonyl,(alkoxy)alkoxycarbonyl, (hydroxyalkoxy)alkoxycarbonyl,((alkoxy)alkoxy)alkoxycarbonyl, tetrazolyl, morpholin-4-ylalkyl, and(1,2)-imidazolinyl (optionally substituted by alkyl)); or R² ispiperazin-1-yl (optionally substituted by one or more substituentsindependently selected from the group consisting of alkyl, carboxy,carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl); or R² is1-piperazinoyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, carboxy, carboxyalkyl,alkoxycarbonyl, and alkoxycarbonylalkyl); or R² is piperidin-1-yl(optionally substituted by one or more substituents selected from thegroup consisting of carboxy, carboxyalkyl, alkoxycarbonyl, andalkoxycarbonylalkyl); or R² is (3,4)-piperidinyloxy (optionallysubstituted by one or more substituents selected from the groupconsisting of alkylcarbonyl, carboxy, alkoxycarbonyl, carboxyalkyl,alkoxycarbonylalkyl, and tetrazolyalkyl); or R² is piperidin-4-ylamino(wherein the amino is optionally substituted by alkyl and thepiperidinyl group is optionally substituted by one or more substituentsselected from the group consisting of alkyl, alkoxycarbonyl,carboxyalkyl, alkoxycarbonylalkyl and aralklyl); or R² is3-pyrrolidinyloxy (optionally substituted by one or more substituentsselected from the group consisting of alkyl, aralkyl, amidino,1-iminoethyl, carboxy, carboxyalkyl, alkoxycarbonyl andalkoxycarbonylalkyl); each R⁸ and R⁹ is independently hydrogen, alkyl,aryl, or aralkyl; R¹¹ is hydrogen, alkyl or halo; and R¹² is alkyl, arylor aralkyl: ##STR10##

Compounds of formulae (N) and (O) may be prepared according to ordinaryskill in the art, or by methods described herein, or may be commerciallyavailable, for example, from Aldrich Chemical Co., Inc.

In general, compounds of formula (P) are prepared in the same manner asdescribed above for compounds of formula (J), except the temperatures atwhich the reaction is run are elevated to between about 50° C. and 130°C. The compounds of formula (P) are isolated from the reaction mixtureby conventional techniques.

B. Preparation of the Compounds of the Invention

In the following Reaction Scheme 6, compounds of formula (Ia) arecompounds of formula (I) as described above in the Summary of theInvention wherein Z¹ and Z² are --O--. As illustrated below in ReactionScheme 6, wherein A is --N═ or --C(R¹¹)═ (where R¹¹ is hydrogen, alkylor halo); R¹ and R³ is hydrogen, halo, alkyl, haloalkyl, alkoxy,haloalkoxy, nitro, --N(R⁸)R⁹, --C(O)OR¹³, --C(O)N(R⁸)R⁹, --C(O)N(R⁸)CH₂C(O)N(R⁸)R⁹, --N(R⁸)C(O)N(R⁸)R⁹, --N(R⁸)C(O)R⁸, --N(R⁸)S(O)₂ R¹², or--N(R⁸)C(O)N(R⁸)CH₂ --C(O)N(R⁸)R⁹ ; R² is hydrogen, alkyl, haloalkoxy,--OR⁸, --C(O)OR¹³, --C(O)N(R⁸)R⁹, --N(R⁸)R⁹, --C(O)N(R⁸)(CH₂)_(m)C(O)OR¹³ (where m is 0 to 3), --N(R⁸)(CH₂)_(n) C(O)OR¹³ (where n is 1 to3), --N((CH₂)_(n) N(R⁸)R⁹)(CH₂)_(n) C(O)OR¹³ (where each n is 1 to 3),--O(CH₂)_(n) C(O)N(R⁸)R⁹ (where n is 1 to 3), --O(CH₂)_(p) C(O)OR¹³(where p is 1 to 6), --N(R⁸)(CH₂)_(n) C(O)N(R⁸)(CH₂)_(n) C(O)OR¹³ (whereeach n is independently 1 to 3), morpholin-4-yl, 3-tetrahydrofuranoxy;or R² is aryloxy (optionally substituted by one or more substituentsindependently selected from the group consisting of --OR⁸,--C(O)N(R⁸)R⁹, halo, alkyl, carboxy, alkoxycarbonyl, haloalkoxy,haloalkoxycarbonyl, alkoxycarbonylalkyl, carboxyalkyl,aminocarbonylalkyl, (alkylamino)carbonylalkyl,(dialkylamino)carbonylalkyl, (arylamino)carbonylalkyl,(aralkylamino)carbonylalkyl, alkoxycarbonylalkenyl, carboxyalkenyl,aminocarbonylalkenyl, (alkylamino)carbonylalkenyl,(dialkylamino)carbonylalkenyl, (arylamino)carbonylalkenyl,(aralkylamino)carbonylalkenyl, (hydroxyalkoxy)carbonyl,(alkoxy)alkoxycarbonyl, (hydroxyalkoxy)alkoxycarbonyl,((alkoxy)alkoxy)alkoxycarbonyl, tetrazolyl, morpholin-4-ylalkyl, and(1,2)-imidazolinyl (optionally substituted by alkyl)); or R² ispiperazin-1-yl (optionally substituted by one or more substituentsindependently selected from the group consisting of alkyl, carboxy,carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl); or R² is1-piperazinoyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, carboxy, carboxyalkyl,alkoxycarbonyl, and alkoxycarbonylalkyl); or R² is piperidin-1-yl(optionally substituted by one or more substituents selected from thegroup consisting of carboxy, carboxyalkyl, alkoxycarbonyl, andalkoxycarbonylalkyl); or R² is (3,4)-piperidinyloxy (optionallysubstituted by one or more substituents selected from the groupconsisting of alkylcarbonyl, carboxy, alkoxycarbonyl, carboxyalkyl,alkoxycarbonylalkyl, and tetrazolylalkyl); or R² is piperidin-4-ylamino(wherein the amino is optionally substituted by alkyl and thepiperidinyl group is optionally substituted by one or more substituentsselected from the group consisting of alkyl, alkoxycarbonyl,carboxyalkyl, alkoxycarbonylalkyl and aralklyl); or R² is3-pyrrolidinyloxy (optionally substituted by one or more substituentsselected from the group consisting of alkyl, aralkyl, amidino,1-iminoethyl, carboxy, carboxyalkyl, alkoxycarbonyl andalkoxycarbonylalkyl); R⁴ and R⁷ are independently hydrogen, halo, alkyl,nitro, --OR⁸, --C(O)OR¹³, --C(O)N(R⁸)R⁹, --N(R⁸)R⁹, or --N(H)C(O)R⁸ ; R⁶is halo, allyl, haloalkyl, haloalkoxy, nitro, amino, ureido, guanidino,--OR⁸, --C(NH)NH₂, --C(NH)NHOH, --C(O)R¹⁰, --(CH₂)_(m) C(O)N(R⁸)R⁹(where m is 0 to 3), --CH(OH)C(O)N(R⁸)R⁹, --(CH₂)_(m) N(R⁸)R⁹ (where mis 0 to 3), --(CH₂)_(m) C(O)OR¹³ (where m is 0 to 3), --N(H)C(O)R⁸,(1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl),(1,2)-imidazolyl (optionally substituted by alkyl), or(1,2)-imidazolinyl (optionally substituted by alkyl); each R⁸ and R⁹ isindependently hydrogen, alkyl, aryl, or aralkyl; R¹⁰ is hydrogen, alkyl,aryl, aralkyl, 1-pyrrolidinyl, 4-morpholinyl, 4-piperazinyl,4-(N-methyl)piperazinyl, or 1-piperidinyl; R¹² is alkyl, aryl oraralkyl; and R¹³ is hydrogen, alkyl or aralkyl; compounds of formula(Ia) are prepared from compounds of formula (Q) as follows: ##STR11##

Compounds of formula (Q) are prepared as described herein above forcompounds of formulae (J), (M), and (P).

In general, compounds of formula (Ia) are prepared from compounds offormula (Q) by dissolving the compound of formula (Q) in an anhydrousalkanol, preferably ethanol and then treating the solution with ananhydrous mineral acid, preferably HCl, while maintaining the reactiontemperatures between about -78° C. and ambient temperature for between 2hours and 24 hours, allowing the temperature to rise to ambienttemperature while monitoring for reaction completion, for example,through thin layer chromatography. The solvent is then removed and theresulting residue dissolved in fresh anhydrous alkanol, preferablyethanol. The resulting solution was then treated with anhydrous ammoniaat ambient pressure or in a sealed flask, at temperatures from betweenambient temperature and 100° C. for about 1 to about 5 hours. Thecompounds of formula (Ia) are then isolated from the reaction mixture bystandard techniques.

Compounds of formula (Ia) wherein R⁶ is --C(NH)NH₂ or --C(NH)NHOH areproduced from the corresponding cyano compounds.

Alternatively, instead of treating the resulting residue above withanhydrous ammonia, the resulting residue may be treated with a compoundof the formula NH₂ OR⁸ to afford the corresponding compound of formula(Ia) wherein R⁵ is --C(NH)N(H)OR⁸.

In addition, compounds of formula (Ia) which contain a --C(O)OR¹³ groupmay be treated under standard transesterification conditions with anphenol or a naphthol (either optionally substituted by halo, alkyl,alkoxy, amino, nitro or carboxy) to produce compounds of the inventionwhich contain a --C(O)OR⁸ group where R⁸ is aryl.

Compounds of formula (Ia) wherein R⁶ is --C(NH)NH₂ or --C(NH)N(H)OR¹³are produced from the corresponding cyano compounds in a similar manneras that described above for the compounds of formula (Ia).

In addition, compounds of formula (Ia) where R¹, R², R³, R⁴, and R⁷contains a --N(R⁸)R⁹ group where R⁸ and R⁹ are hydrogen, can be treatedwith the appropriate alkylating agents to afford the correspondingcompounds of formula (Ia) where R¹, R², R³, R⁴, and R⁷ contains--N(R⁸)R⁹, --N(R⁸)S(O)₂ R¹², --N(R⁸)C(O)N(R⁸)R⁹, --N(R⁸)C(O)N(R⁸)CH₂--C(O)N(R⁸)R⁹, or --N(R⁸)C(O)R⁸ where each R⁸ and R⁹ is independentlyhydrogen, alkyl, aryl or aralkyl, and R¹² is alkyl, aryl or aralkyl.

Compounds of formula (Ia) may be further treated with the appropriateacid halide, preferably acid chloride, or with the appropriate acidanhydride or an equivalent, to yield compounds of the invention whereinR⁵ is --C(NH)N(H)C(O)R⁸ where R⁸ is hydrogen, alkyl, aryl or aralkyl.

Alternatively, compounds of formula (Ia) may further be treated withcarbamoyl chlorides or their equivalents to yield compounds of theinvention where R⁵ is --C(NH)N(H)C(O)OR¹² where R¹² is alkyl, aryl oraralkyl.

Alternatively, compounds of formula (Ia) may be further treated withcompounds of the formula R¹² --S(O)₂ -imidazole where R¹⁶ is describedin the Summary of the Invention in a polar solvent, such as methyleneclioride, at ambient temperature to afford compounds of the inventionwhere R⁵ is --C(NH)N(H)S(O)₂ R¹².

Alternatively, compounds of formula (Ia) may be further treated with anappropriatly N--R⁹ -substituted phenylcarbamate in a polar solvent,preferably methylene chloride, at ambient temperature, for about 6 to 24hours, preferably for about 12 hours, to afford compounds of theinvention where R⁵ is --C(NH)N(H)C(O)N(R⁸)R⁹.

Compounds of formula (Ia) wherein R¹, R² or R³ contains --C(O)N(R⁸)R⁹ or--C(O)OR¹³ where each R⁸ and R⁹ are independently alkyl, haloalkyl, arylor aralkyl, and R¹³ is alkyl or aralkyl may be hydrolyzed under acidicconditions to prepare compounds of formula (Ia) where R¹, R² or R³contains --C(O)OR⁸ where R⁸ is hydrogen.

Under the same conditions as previously described, compounds of formula(Ia) where R¹, R² or R³ contains --C(O)OR¹³ where R¹³ is hydrogen,alkyl, or aralkyl, may be amidated to form compounds of formula (Ia)where R¹, R² or R³ contains --C(O)N(R⁸)R⁹ where R⁸ and R⁹ areindependently hydrogen, alkyl, aryl or aralkyl.

Compounds of formula (Ia) where R⁴ is --OR⁸ where R⁸ is alkyl, aryl oraralkyl, may be converted to compounds of formula (Ia) where R⁴ is --OR⁸where R⁸ is hydrogen by treatment with boron tribromide in an aproticsolvent, for example, methylene chloride, at temperatures at firstbetween -80° C. and 0° C., then at ambient temperature, for about 4hours to about 16 hours.

Alternatively, compounds of formula (Ia) where R⁴ is --OR⁸ where R⁸ isarylmethyl, preferably, benzyl, may be treated with hydrogen and theappropriate catalyst, for example, palladium on carbon, to givecompounds of formula (Ia) where R⁴ is --OR⁸ where R⁸ is hydrogen.

Compounds of formula (Ia) where R² is 3-pyrrolidinyloxy substituted byarylmethyl on the nitrogen may be treated under standard hydrogenolysisconditions to remove the arylmethyl group to produce compounds offormula (Ia) where R² is unsubstituted 3-pyrrolidinyloxy, which can thenbe reacted with the appropriate imidate to produce the compounds offormula (Ia) where R² is 3-pyrrolidinyloxy substituted by 1-iminoethyl,or with the appropriate haloalkyl esters to produce the compounds offormula (Ia) where R² is 3-pyrrolidinyloxy substituted byalkoxycarbonylalkyl.

In summary, compounds of the invention, are prepared by:

1) reacting a compound of formula (A) as described above with a compoundof formula (B) as described above under the conditions as describedabove to produce a compound of formula (C) as described above, which isan intermediate in the preparation of the compounds of the invention; or

2) reacting a compound of formula (D) as described above with a compoundof formula (E) as described above under conditions as described above toproduce a compound of formula (F) as described above, which is anintermediate in the preparation of the compounds of the invention; or

3) reacting a compound of formula (G) as described above, which can be acompound of formula (C) as described above or a compound of formula (F)as described above, with a compound of formula (H) as described aboveunder conditions as described above to produce a compound of formula (J)or a compound of formula (K) as described above, which are intermediatesin the preparation of the compounds of the invention; then

4) reacting a compound of formula (K) as described above with a compoundof formula (L) as described above under conditions as described above toproduce a compound of formula (M) as described above, which is anintermediate in the preparation of the compounds of the invention; or

5) reacting a compound of formula (N) as described above with a compoundof formula (O) as described above under conditions as described above toproduce a compound of formula (P) as described above, which is anintermediate in the preparation of the compounds of the invention: then

6) reacting a compound of formula (Q) as described above, which can be acompound of formula (J), a compound of formula (M) or a compound offormula (P) as described above, with the appropriate reagent under theconditions as described above to form compounds of formula (Ia) asdescribed above.

Similar reactions may be performed on similar starting materials andintermediates to produce the corresponding compounds of the inventionsnot depicted in the Reaction Schemes above.

In addition, all compounds of the invention that exist in free base formor free acid form may be converted to their pharmaceutically acceptablesalts by treatment with the appropriate inorganic or organic acid, or bythe appropriate inorganic or organic base. Salts of the compounds of theinvention can also be converted to the free base form or to the freeacid form or to another salt.

The following specific preparations and examples are provided as a guideto assist in the practice of the invention, and are not intended as alimitation on the scope of the invention.

PREPARATION 1 4-Methoxy-2,3,5,6-tetrafluoropyridine

A. To pentafluoropyridine (1.0 g, 5.9 mmol) in petroleum ether (60 mL)at 0° C. was added sodium methoxide (0.32 mg, 5.9 mmol). After stirringfor 12 hours at ambient temperature, the reaction was washed with water,dried (MgSO₄), and the solvent was removed in vacuo to give4-methoxy-2,3,5,6-tetrafluoropyridine; NMR (CDCl₃) 4.3 ppm.

B. In a similar manner, the following compounds were made:

2,3,5,6-tetrafluoro-4-(2,2,2-trifluoroethoxy)pyridine; and

2,3,5,6-tetrafluoro-4-(1,3-difluoroprop-2-oxy)pyridine.

PREPARATION 2 4-Dimethylamino-2,3,5,6-tetrafluoropyridine

A. To methylene chloride (50 mL) cooled in an ice bath was addedpentafluoropyridine (2.0 g, 11.8 mmol) and dimethylamine (2.97 mL of a40% solution in water, 24 mmol). After stirring for 30 minutes thesolution was washed with water, and dried over basic alumina. Thesolvent was removed in vacuo to give4-dimethylamino-2,3,5,6-tetrafluoropyridine; NMR (CDCl₃) 3.13 (m,6) ppm.

B. In a similar manner, the following compounds were made:

1-(2,3,5,6-tetrafluoropyridin-4-yl)piperidine-4-carboxylic acid, ethylester; NMR (CDCl₃) 4.15 (q,2), 3.7 (m,2), 3.25 (m,2), 2.55 (m,1), 2.05(m,2), 1.9 (m,2), 1.15 (t,3) ppm;

1-(2,3,5,6-tetrafluoropyridin-4-yl)piperidine-3-carboxylic acid, ethylester; NMR (CDCl₃) 4.15 (q,2), 3.8 (m,1), 3.55 (m,1), 3.4 (m,1), 3.25(m,1), 2.7 (m,1), 2.15 (m,1), 91.8 (m,3), 1.15 (t,3) ppm;

4-(piperidin-1-yl)-2,3,5,6-tetrafluoropyridine; NMR (CDCl₃) 3.4 (m,4),1.7 (m,6) ppm;

4-(4-methylpiperazin-1-yl)-2,3,5,6-tetrafluoropyridine; NMR (CDCl₃) 3.45(m,4), 2.5 (m,4), 2.3 (s,3) ppm;

4-(2,3,5,6-tetrafluoropyridin-4-yl)piperazine-1-acetic acid, ethylester; NMR (CDCl₃) 4.2 (q,2), 3.55 (m,4), 3.3 (s,2), 2.7 (m,4), 1.3(t,3) ppm;

N-methyl-N-(2,3,5,6-tetrafluoropyridin-4-yl)glycine, ethyl ester; and

4-(morpholin-1-yl)-2,3,5,6-tetrafluoropyridine.

PREPARATION 3 1-[(2,6-Dichloropyridin-4-yl)carbonyl]-4-methylpiperazine,Hydrochloride

To methylene chloride (15 mL) was added 2,6-dichloropyridine-4-carbonylchloride (1.0 g, 4.8 mmol) and 1-methylpiperazine (0.48 g, 4.8 mmol).After stirring for 1 day, the reaction was poured into ether. Theresulting solid was filtered to give1-[(2,6-dichloropyridin-4-yl)carbonyl]-4-methylpiperazine,hydrochloride.

PREPARATION 4 3-(1-Methylimidazolin-2-yl)phenol, Hydrobromide

A. To ethanol (200 mL) was added 3-methoxybenzonitrile (10.9 g, 82mmol). The solution was cooled in an ice bath and HCl (g) was bubbledinto the solution. The reaction was warmed to ambient temperature andstirred for 2 days. The solvent was removed in vacuo and the residue wasslurried in ethanol (20 mL). N-methylethylene-diamine (12 g, 160 mmol)was added and the reaction was refluxed for 7 hours. The solvent wasremoved in vacuo and the residue was chromatographed on silica gel withmethylene chloride/methanol/ammonium hydroxide (20/1/0.1). The resultingoil was dissolved in 48% HBr (20 mL) and refluxed for 19 hours. Themixture was cooled to ambient temperature and the solvent was removed invacuo to give 3-(1-methylimidazolin-2-yl)phenol, hydrobromide.

B. In a similar manner, the following compound is made:

3-(1-methyltetrahydropyrimidin-2-yl)phenol, hydrobromide.

PREPARATION 5 3,3'-[2,6-Pyridinediylbis(oxy)]bis(benzonitrile)

A. To sodium hydride (0.38 g, 9.5 mmol) in N,N-dimethylformamide (3 mL)was added 3-cyanophenol (1.1 g, 8.9 mmol) and 2,6-difluoropyridine (0.4mL, 4.4 mmol). After heating in an oil bath at 100° C. for 15 hours thereaction was partitioned with ethyl acetate and water. The organic layerwas separated, washed with water, dried (Na₂ SO₄), and the solvent wasremoved in vacuo. The residue was chromatographed on silica gel (50 g)with methylene chloride/hexane (3/1) to give3,3'-[2,6-pyridinediylbis(oxy)]bis(benzonitrile). Recrystallization fromethyl acetate/hexane gave pure3,3'-[2,6-pyridinediylbis(oxy)]bis(benzonitrile); NMR (CDCl₃) 7.79(t,1), 7.45 (m,4), (m,4), 6.72 (d,2) ppm.

B. In a similar manner, the following compounds were made:

4,4'-[2,6-pyridinediylbis(oxy)]bis(benzonitrile); NMR (CDCl₃) 7.8 (t,1),7.6 (d,4), 7.2 (d,4), 6.8 (d,2) ppm;

3,3'-[3,5-dichloro-2,6-pyridinediylbis(oxy)]bis(benzonitrile); NMR(CDCl₃) 7.9 (s,1), 7.45 (m,4), 7.2 (m,4) ppm;

4,4'-[3,5-dichloro-2,6-pyridinediylbis(oxy)]bis(benzonitrile); NMR(CDCl₃) 7.95 (s,1), 7.6 (d,4), 7.1 (d,4) ppm;

2,6-bis(3-cyanophenoxy)pyridine-4-carboxylic acid, ethyl ester; NMR(CDCl₃) 7.45 (m,4), 7.35 (m,6), 4.45 (q,2), 1.45 (t,3) ppm;

2,6-bis(3-cyanophenoxy)pyridine-3-carboxylic acid, ethyl ester; NMR(CDCl₃) 8.4 (d,1), 7.45 (m,4), 7.25 (m,4), 6.75 (d,1), 4.4 (q,2), 1.45(t,3) ppm;

3,3'-[3,5-difluoro-2,6-pyridinediylbis(oxy)]bis(benzonitrile); NMR(CDCl₃) 7.55 (t,1), 7.45 (m,4), 7.29 (m,4) ppm;

3,3'-[2,6-pyrazinediylbis(oxy)]bis(benzonitrile); NMR (CDCl₃) 8.2 (s,2),7.5 (m,4), 7.3 (m,4) ppm;

3,3'-[2,6-pyrimidinediylbis(oxy)]bis(benzonitrile); NMR (CDCl₃) 8.4(d,1), 7.5 (m,4), 7.4 (m,4), 6.8 (d,1) ppm;

3,3'-[3,5-difluoro-4-methyl-2,6-pyridinediylbis(oxy)]bis(benzonitrile);NMR (CDCl₃) 7.44 (m,4), 7.27 (m,4), 2.4 (s,3) ppm;

3,3'-[4-nitro-1,3-phenylenebis(oxy)]bis(benzonitrile); NMR (CDCl₃) 8.13(d,1), 7.5 (m,4), 7.3 (m,4), 6.84 (dd,1), 6.69 (d,1) ppm; and

3,3'-[3-trifluoromethyl-2,6-pyridinediylbis(oxy)]bis(benzonitrile); NMR(CDCl₃) 8.05 (t,1), 7.5 (m,4), 7.3 (m,4), 6.8 (d,1) ppm.

PREPARATION 6 3-[(3,5,6-Trifluoro-4-methylpyridin-2-yl)oxy]benzonitrile

A. To 2,3,5,6-tetrafluoro-4-methylpyridine (0.71 g, 4.3 mmol) dissolvedin acetonitrile (5 mL) was added 3-cyanophenol (0.5 g, 4.2 mmol) andcesium carbonate (1.44 g, 4.4 mmol). The reaction was heated in an oilbath at 45° C. for 16 hours and partitioned with ether and water. Theorganic layer was separated, washed with brine, dried (Na₂ SO₄), and thesolvent removed in vacuo.

Chromatography on silica gel with methylene chloride/hexane (7/3) gave3-[(3,5,6-trifluoro-4-methylpyridin-2-yl)oxy]benzonitrile; NMR (CDCl₃)7.55 (m,2), 7.45 (m,2), 2.24 (s,3) ppm.

B. In a similar manner, the following compounds were made:

4-[(2,3,5,6-tetrafluoropyridin-4-yl)oxy]-3-methoxybenzoic acid, ethylester;

3-(4-dimethylamino-3,5,6-trifluoropyridin-2-yl)-4-methoxybenzonitrile;NMR (CDCl₃) 7.55 (d,1), 7.4 (s,1), 7.05 (d,3), 3.85 (s,3), 3.15 (s,6)ppm;

1-[(2-(5-cyano-2-methoxyphenoxy)-3,5,6-trifluoropyridin-4-yl)piperidine-4-carboxylicacid, ethyl ester; NMR (CDCl₃) 7.5 (d,1), 7.4 (s,1), 7.05 (d,1), 4.15(q,2), 3.8 (s,3), 3.7 (m,2), 3.25 (m,2), 2.55 (m,1), 2.1 (m,2), 1.9(m,2), 1.15 (t,3) ppm;

1-[(2-(5-cyano-2-methoxyphenoxy)-3,5,6-trifluoropyridin-4-yl)piperidine-3-carboxylicacid, ethyl ester; NMR (CDCl₃) 7.5 (d,1), 7.4 (s,1), 7.05 (d,1), 4.15(q,2), 3.8 (s,3), 3.7 (m,1), 3.55 (m,1), 3.4 (m,1), 3.25 (m,1), 2.7(m,1), 2.15 (m,1), 1.8 (m,3), 1.15 (t,3) ppm;

2-chloro-6-(5-cyano-2-methoxyphenoxy)pyridine-4-carboxylic acid, ethylester; NMR (CDCl₃) 7.6 (m,2), 7.4 (m,2), 7.0 (d,2), 4.4 (q,2), 3.8(s,3), 1.4 (t,3) ppm;

2-chloro-6-(3-dimethylaminophenoxy)pyridine-4-carboxylic acid, ethylester; NMR (CDCl₃) 7.6 (s,1), 7.2 (m,2), 6.6 (d,1), 6.5 (m,2), 4.4(q,2), 3.0 (s,6), 1.14 (t,3) ppm;

4-benzyloxy-3-(4-(piperidin-1-yl)-3,5,6-trifluoropyridin-2-yl)benzonitrile;NMR (CDCl₃) 7.5 (m,2), 7.35 (m,3), 7.2 (m,2), 7.05 (d,1), 5.1 (s,2), 3.4(m,4), 1.75 (m,6) ppm;

4-benzyloxy-3-(4-(4-methylpiperazin-1-yl)-3,5,6-trifluoropyridin-2-yl)benzonitrile;NMR (CDCl₃) 7.5 (m,2), 7.35 (m,3), 7.2 (m,2), 7.05 (d,1), 5.1 (s,2), 3.4(m,4), 2.5 (m,4), 2.35 (s,3) ppm;

1-[(2-(5-cyano-2-methoxyphenoxy)-6-chloropyridin-4-yl)carbonyl]-4-methylpiperazine;NMR (CDCl₃) 7.44 (dd,1), 7.3 (d,1), 6.95 (d,1), 6.9 (s,1), 6.74 (s,1),3.7 (s,3), 3.7 m.2), 3.3 (m,2), 2.4 (m,2), 2.3 (m,2), 2.2 (s,3) ppm;

4-[(2-(5-cyano-2-benzyloxyphenoxy)-3,5,6-trifluoropyridin-4-yl)piperazine-1-aceticacid, ethyl ester; NMR (CDCl₃) 7.5 (m,2), 7.35 (m,3), 7.2 (m,2), 7.05(d,1), 5.1 (s,2), 4.2 (q,2), 3.5 (m,4), 3.3 (s,2), 2.75 (m,4), 1.3 (t,3)ppm;

3-[(3,5,6-trifluoro-4-methylpyridin-2-yl)oxyl-4-methoxybenzonitrile; NMR(CDCl₃) 7.6 (d,1), 7.4 (s,1), 7.0 (d,1), 3.8 (s,3), 2.4 (s,3) ppm;

3-[(3,5,6-trifluoro-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy]N,N-dimethylbenzamide;NMR (CDCl₃) 7.4 (m,1), 7.2 (d,1), 7.3 (m,1), 7.1-7.2 (m,2), 4.7 (q,2),3.1 (s,3), 3.0 (s,3) ppm;

3-[(4-(1,3-difluoroprop-2-oxy)-3,5,6-trifluoropyridin-2-yl)oxy]-N,N-dimethylbenzamide;

N-(2-(5-cyano-2-methoxyphenoxy)-3,5,6-trifluoropyridin-4-yl)-N-methylglycine,ethyl ester;

N-(2-(3-cyanophenoxy)-3,5,6-trifluoropyridin-4-yl)-N-methylglycine,ethyl ester;

3-(4-(morpholin-1-yl)-3,5,6-trifluoropyridin-2-yl)oxy)-4-(benzyloxy)benzonitrile;

2-chloro-6-(3-dimethylaminocarbonylphenoxy)pyridine-4-carboxylic acid,ethyl ester; NMR (CDCl₃) 7.59 (s,1), 7.46 (t,1), 7.38 (s,1), 7.32 (d,1),7.21 (s,1), 7.2 (d,1), 4.42 (q,2), 3.05 (s,3), 2.88 (s,3), 1.20 (t,3)ppm;

3-[(6-fluoropyridin-2-yl)oxy]-N,N-dimethylbenzamide; NMR (CDCl₃) 7.75(q,1), 7.43 (m,1), 7.27 (m,1), 7.2 (m,2), 6.75 (m,1), 6.62 (d,1), 3.1(s,3), 3.0 (s,3) ppm;

4-[(2-(5-cyano-2-benzyloxyphenoxy)-3,5,6-trifluoropyridin-4-yl)oxy]-3-methoxybenzoicacid, ethyl ester; and

4-[(2-(5-cyano-2-benzyloxyphenoxy)-3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)pyridin-4-yl)oxy]-3-methoxybenzoicacid, ethyl ester.

PREPARATION 73-[(3,5-Difluoro-6-(5-dimethylamino-2-methylphenoxy)-4-methylpyridin-2-yl)oxy]benzonitrile

A. In a manner similar to preparation 6, reaction of3-(3,5,6-trifluoro-4-methylpyridin-2-yl)benzonitrile (1.1 g, 4.4 mmol),5-dimethylamino-2-methylphenol (0.66 g, 4.4 mmol), and cesium carbonate(1.7 g, 5.2 mmol) in acetonitrile (10 mL) gave3-[(3,5-difluoro-6-(5-dimethylamino-2-methylphenoxy)-4-methylpyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.3 (m,4), 7.0 (d,1), 6.5 (d,1), 6.3 (s,1), 2.8 (s,6),2.4(s,3), 2.0 (s,3) ppm.

B. In a similar manner, the following compounds were made:

3-[(3,5-difluoro-6-(3-dimethylamino-2-methylphenoxy)-4-methylpyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.1-7.5 (m,5), 6.9 (d,1), 6.65 (d,1), 6.3 (s,1), 2.6 (s,6),2.4 (s,3), 2.0 (s,3) ppm;

3,3'-[3,5-difluoro-4-methoxy-2,6-pyridinediylbis(oxy)]bis(benzonitrile);NMR CDCl₃) 7.45 (m,4), 7.3 (m,4), 4.3 (s,3) ppm;

3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-4-methoxybenzenecarboxylicacid; NMR (CDCl₃) 7.9 (d,1), 7.7 (s,1), 7.2 (m,4), 6.95 (d,1), 3.85(s,3), 2.4 (s,3) ppm;

3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-4,5-dimethoxybenzene-carboxylicacid, ethyl ester; NMR (CDCl₃) 7.4 (s,1), 7.2-7.4 (m,5), 4.35 (q,2), 3.9(s,3), 3.8 (s,3), 2.4 (s,3) ppm;

3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-4-methylbenzoicacid; NMR (CDCl₃) 7.75 (d,1), 7.55 (s,1), 7.1-7.3 (m,5), 2.4 (s,3), 2.2(s,3) ppm;

5-[6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzene-1,3-dicarboxylicacid, diethyl ester; NMR (CDCl₃) 8.45 (s,1), 7.85 (s,2), 7.25 (m,4), 4.4(q,4), 2.4 (s,3), 1.4)t,6) ppm;

4-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxyl-3-methoxybenzoicacid; NMR (CDCl₃) 7.65 (dd,1), 7.62 (d,1), 7.33 (dt,1), 7.27 (dt,1),7.18 (m,2), 7.05 (d,1), 3.8 (s,3), 2.4 (s,3) ppm;

3,3'-[3-nitro-2,6-pyridinediylbis(oxy)]bis(benzonitrile); NMR (CDCl₃)8.6 (d,1), 7.5 (m,4), 7.2 (m,4), 6.8 (d,1) ppm;

3-[(3,5-difluoro-6-(4-dimethylaminomethylphenoxy)-4-methylpyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.3 (m,5), 7.15 (m,1), 6.9 (m,2), 3.35 (s,2), 2.4 (s,3),2.15 (s,6) ppm;

3-[(3,5-difluoro-4-methyl-6-(3-(morpholin-4-yl)phenoxy)pyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.1-7.4 (m,5), 6.7 (d,1), 6.5 (s,1), 3.8 (m,4), 3.1 (m,4),2.4 (s,3) ppm;

3-[(3,5-difluoro-6-(3-(2-(1H-imidazol-1-yl)-1-oxoethyl)phenoxy)-4-methylpyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.8 (d,1), 7.7 (s,1), 7.5 (m,2), 7.3 (m,5), 7.1 (s,1), 7.0(s,1), 5.45 (s,2), 2.4 (s,3) ppm;

4-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzoicacid; NMR (CDCl₃) 8.05 (d,2), 7.2-7.5 (m,4), 7.1 (d,2), 2.4 (s,3) ppm;

3-[3,5-difluoro-4-methyl-6-(3-((phenyl)oxomethyl)phenoxy)pyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.75 (d,2), 7.4-7.6 (m,6), 7.3 (m,5); 2.4 (s,3) ppm;

3-[(3,5-difluoro-6-(3-hydroxyphenoxy)-4-methylpyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.35 (m,4), 7.2 (t,1), 6.65 (dd,1), 6.6 (m,2), 5.65 (s,1),2.4 (s,3) ppm;

5-[(3,5-diflouro-6-(3-dimethylaminophenoxy)-4-methylpyridin-2-yl)oxy]-2-methoxybenzonitrile;NMR (CDCl₃) 7.4 (d,1), 7.3 (s,1), 7.03 (t,1), 6.8 (d,1), 6.43 (d,1),6.25 (s,1), 6.18 (d,1), 3.68 (s,3), 2.85 (s,6), 2.45 (s,3) ppm;

3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzeneaceticacid, ethyl ester; NMR (CDCl₃) 7.3 (m,5), 7.05 (d,1), 6.9 (m,2), 3.65(s,3), 3.6 (s,2), 2.4 (s,3) ppm;

3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzenepropionicacid; NMR (CDCl₃) 7.3 (m,5), 7.05 (d,1), 6.85 (m,2), 2.9 (t,2), 2.6(t,2), 2.4 (s,3) ppm;

3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-methylpyridin-2-yl)oxy]-2,6-dimethoxybenzonitrile;NMR (CDCl₃) 7.3 (d,1), 7.0 (t,1), 6.55 (d,1), 6.4 (d,1), 6.2 (m,2), 3.9(s,3), 3.7 (s,3), 2.9 (s,6), 2.4 (s,3) ppm;

3-[(3,5-difluoro-6-(3-(2-hydroxyethyl)phenoxy)-4-methylpyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.2-7.4 (m,5), 7.0 (d,1), 6.85 (m,2), 3.75 (t,2), 2.8 (t,2),2.4 (s,3) ppm;

3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-N,N-dimethylbenzene-propionamide;NMR (CDCl₃) 7.45 (d,1), 7.1-7.4 (t,4), 7.0 (d,1), 6.85 (m,1), 6.85(m,1), 6.8 (d,1), 3.9 (s,3), 3.85 (s,3), 3.85 (m,2), 2.5 (t,2), 2.35(s,3) ppm;

3-[(3,5-difluoro-6-(3-(hydroxymethyl)phenoxy)-4-methylpyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.3-7.5 (m,5), 7.2 (d,1), 7.1 (s,1), 6.95 (d,1), 4.7 (s,2),2.4 (s,3) ppm;

3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-N,N-dimethylbenzamide;NMR (CDCl₃) 7.2-7.4 (m,5), 7.0 (m,1), 6.9 (m,2), 3.65 (s,2), 2.95 (s,6),2.35 (s,3) ppm;

3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.35 (m,2), 7.25 (m,2), 7.2 (t,1), 7.0 (d,1), 6.85 (m,2),2.9 (t,2), 2.45 (t,2), 2.4 (s,3) ppm;

4-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-α-hydroxybenzeneaceticacid; NMR (CDCl₃) 7.25 (m,6), 7.15 (s,1), 6.95 (m,1), 5.2 (s,1), 2.4(s,3) ppm;

3-[3,5-difluoro-4-methyl-6-(3-(1-oxoethyl)phenoxy)pyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.75 (dt,1), 7.59 (m,1), 7.44 (t,1), 7.2-7.4 (m,5), 2.57(s,3), 2.40 (s,3) ppm;

3-[(3,5-difluoro-4-methyl-6-(3-(2-methyl-1-oxopropyl)phenoxy)pyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.75 (d,1), 7.6 (m,1), 7.45 (t,1), 7.2-7.4 (m,5), 3.45(m,1), 2.4 (s,3), 1.25 (m,6) ppm;

3-[(3,5-difluoro-4-methyl-6-(3-(1-methylethoxy)phenoxy)pyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.2-7.5 (m,5), 6.7 (d,1), 6.55 (m,2), 4.45 (m,1), 2.4 (s,3),1.3 (m,6) ppm;α-acetoxy-4-[(6-(3-cyanophenoxy)-3,5-difuoro-4-methylpyridin-2-yl)oxy]-N,N-dimethyl-benzeneacetamide;NMR (CDCl₃) 7.3 (m,6), 7.15 (m,1), 7.0 (m,1), 6.1 (s,1), 2.9 (s,3), 2.85(s,3), 2.40 (s,3), 2.1 (s,3) ppm;

4-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-α-ethoxybenzeneaceticacid, methyl ester; NMR (CDCl₃) 7.0-7.5 (m,8), 4.75 (s,1), 3.75 (s,3),3.35 (s,3), 2.4 (s,3) ppm;

3-[(6-(5-cyano-2-methoxyphenoxy)-3,5-difluoro-4-dimethylaminopyridin-2-yl)oxy]-N,N-dimethylbenzamide;NMR (CDCl₃) 7.4 (m,2), 7.1 (d,1), 6.95 (m,3), 3.8 (s,3), 3.1 (s,6), 3.05(s,3), 2.9 (s,3) ppm;

1-[(2-(5-cyano-2-methoxyphenoxy)-3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)pyridin-4-yl]piperidine-4-carboxylicacid, ethyl ester; NMR (CDCl₃) 7.4 (d,1), 7.2 (m,2), 7.1 (d,1), 6.9(m,3), 4.15 (q,2), 3.75 (s,3), 3.7 (m,2), 3.25 (m,2), 3.1 (s,3), 2.95(s,3), 2.55 (m,1), 2.0 (m,4), 1.15 (t,3) ppm;

1-[(2-(5-cyano-2-methoxyphenoxy)-3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)pyridin-4-yl]piperidine-3-carboxylicacid, ethyl ester; NMR (CDCl₃) 7.4 (d,1), 7.3 (m,2), 7.1 (d,1), 6.9(m,3), 4.15 (q,2), 3.8 (m,1), 3.75 (s,3), 3.6 (m,1), 3.4 (m,1), 3.25(n,1), 3.1 (s,3), 2.9 (s,3), 2.7 (m,1), 2.15 (m,1), 1.8 (m,3), 1.15(t,3) ppm;

3-[(6-(5-cyano-2-benzyloxyphenoxy)-3,5-difluoro-4-(piperidin-1-yl)pyridin-2-yl)oxy]-N,N-dimethylbenzamide;NMR (CDCl₃) 7.4 (m,5), 7.2 (m,3), 7.1 (m,1), 6.95 (m,3), 5.1 (s,2), 3.4(m,4), 3.1 (s,3), 2.9 (s,3), 1.75 (m,6) ppm;

3-[(6-(5-cyano-2-benzyloxyphenoxy)-3,5-difluoro-4-(4-methylpiperazin-1-yl)pyridin-2-yl)oxy]-N,N-dimethylbenzamide;NMR (CDCl₃) 7.2 (m,9), 6.95 (m,3), 5.1 (s,2), 3.5 (m,4), 3.1 (s,3), 2.9(s,3), 2.6 (m,4), 2.4 (s,3) ppm;

4-[(2-(5-cyano-2-benzyloxyphenoxy)-3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)pyridin-4-yl]piperazine-1-aceticacid, ethyl ester; NMR (CDCl₃) 7.3 (m,5), 7.15 (m,4), 6.95 (m,3), 5.1(s,2), 4.2 (q,2), 3.5 (m,4), 3.3 (s,2), 3.1 (s,3), 28 (s,3), 2.75 (m,4),1.3 (t,3) ppm;

1-[(2-(5-cyano-2-methoxyphenoxy)-6-(3-dimethylaminocarbonylphenoxy)pyridin-4-yl)carbonyl]-4-methylpiperazine;NMR (CDCl₃) 7.4 (dd,1), 7.27 (m,2), 7.16 (m,1), 7.0 (m,2), 6.9 (d,1),6.63 (s,1), 6.55 (s,1), 3.8 (m,2), 3.8 (s,3), 3.5 (m,2), 3.1 (s,3), 2.9(s,3), 2.5 (m,2), 2.4 (m,2), 2.4 (s,3) ppm;

1-[(2-(5-cyano-2-methoxyphenoxy)-6-chloropyridin-4-yl)carbonyl]-4-methylpiperazine;NMR (CDCl₃) 7.44 (dd,1), 7.3 (d,1), 6.95 (d,1), 6.9 (s,1), 6.74 (s,1),3.7 (s,3), 3.7 (m,2), 3.3 (m,2), 2.4 (m,2), 2.3 (m,2), 2.2 (s,3) ppm;

2-(5-cyano-2-methoxyphenoxy)-6-(3-(imidazol-1-yl)phenoxy)pyridine-4-carboxylicacid, ethyl ester; NMR (CDCl₃) 7.8 (s,1), 7.3 (m,3), 7.2 (m,5), 7.0(m,2), 6.7 (d,1), 4.4 (q,2), 3.7 (s,3), 1.4 (t,3) ppm;

2-(5-cyano-2-methoxyphenoxy)-6-(3-dimethylaminophenoxy)pyridine-4-carboxylicacid, ethyl ester; NMR (CDCl₃) 7.4 (d,1), 7.3 (s,1), 7.2 (s,1), 7.1(t,1), 7.0 (s,1), 6.8 (d,1), 6.5 (d,1), 6.3 (m,2), 4.4 (q,2), 3.7 (s,3),2.8 (s,6), 1.4 (t,3) ppm;

3-[(6-(5-cyano-2-methoxyphenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-N,N-dimethylbenzamide;NMR (CDCl₃) 8.00 (bs,1), 7.40 (dt,1), 7.25 (t,1), 7.21 (dt,1), 7.25(t,1), 7.21 (dt,1), 7.08 (bd,1), 6.91 (bs,1), 6.87 (td,1), 3.74 (s,3),2.92 (s,3), 2.85 (s,3), 2.39 (s,3) ppm

3-[(6-(2-amino-5-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-N,N-dimethylbenzamide;NMR (CDCl₃) 7.5 (t,1), 7.2-7.0 (m,5), 6.6 (d,1), 4.6 (s,2), 3.1 (s,3),2.9 (s,3), 2.0 (s,3) ppm;

3-[(6-(2-amino-5-cyanophenoxy)-3,5-difluoro-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy]-N,N-dimethylbenzamide;NMR (CDCl₃) 7.3 (dd,1), 7.2 (d,1), 7.1 (m,2), 7.0-7.1 (m,2), 6.6 (d,1),4.8 (q,2), 4.6 (s,2), 3.1 (s,3), 2.9 (s,3) ppm;

3-[(6-(5-cyano-2-methoxyphenoxy)-3,5-difluoro-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy]-N,N-dimethylbenzamide;NMR (CDCl₃) 7.4 (dd,1), 7.3 (d,1), 7.2 (t,1), 7.1 (d,1), 6.9-7.0 (m,2),6.9 (d,1), 4.7 (q,2), 3.7 (s,3), 3.1 (s,3), 2.9 (s,3) ppm; and

3-[(6-(5-cyano-2-methoxyphenoxy)-4-(1,3-difluoroprop-2-oxy)-3,5-difluoropyridin-2-yl)oxy]-N,N-dimethylbenzamide;NMR (CDCl₃) 7.4 (dd,1), 7.3 (d,1), 7.2 (t,1), 7.1 (d,1), 6.9-7.0 (m,2),6.9 (d,1), 5.0 (m,1), 4.9 (d,2), 4.7 (d,2), 3.7 (s,3), 3.1 (s,3), 2.9(s,3) ppm.

PREPARATION 8 4-(6-Fluoropyridin-2-yl)oxy-3-methoxybenzonitrile

A. To 4-hydroxy-3-methoxybenzonitrile (2.6 g, 17 mmol) in DMSO (15 mL)was added sodium hydride (0.44 g, 18 mmol) and 2,6-difluoropyridine (1.0g, 8.7 mmol). After heating at 100° C. for 18 hours the reaction waspartitioned with ethyl acetate and water. The organic layer wasseparated, washed with water, dried (Na₂ SO₄), and the solvent wasremoved in vacuo to give4-(6-fluoropyridin-2-yl)oxy-3-methoxybenzonitrile (1.3 g); NMR (CDCl₃)7.8 (q,1), 7.35 (m,1), 7.25 (m,2), 6.85 (d,1), 6.65 (m,1), 3.85 (s,3)ppm.

B. In a similar manner, the following compounds were made:

3-[(4-methyl-3,5,6-trifluoropyridin-2-yl)amino]benzonitrile; NMR (CDCl₃)8.05 (s,1), 8.95 (d,1), 7.6 (d,1), 7.45 (t,1), 7.25 (s,1), 2.3 (s,3)ppm;

2-chloro-6-(3-cyanophenoxy)pyridine-4-carboxylic acid, ethyl ester, NMR(CDCl₃) 7.80-7.38 (m,6), 4.41 (q,2), 1.92 (t,3) ppm;

2-chloro-6-(5-cyano-2-methoxyphenoxy)-N,N-dimethylpyridine-4-carboxamide;NMR (CDCl₃) 7.2 (m,5), 3.84 (s,3), 3.13 (s,3), 2.95 (s,3) ppm; and

2-chloro-6-(5-cyanophenoxy)-N,N-dimethylpyridine-4-carboxamide; NMR(CDCl₃) 7.45 (m,3), 7.08 (s,1), 6.87 (s,1), 6.67 (s,1), 3.14 (s,3), 3.00(s,3) ppm.

PREPARATION 9 2-Methoxy-3',4-[2,6-pyridinediylbis(oxy)]benzonitrile

A. To 4-(6-fluoropyridin-2-yl)oxy-3-methoxybenzonitrile (0.65 g, 2.7mmol) in DMSO (15 mL) was added 3-cyanophenol (0.32 g, 0.91 mmol) andsodium hydride (0.070 g, 2.9 mmol). After heating at 140° C. for 2 days,the reaction was poured into water and the precipitate was filtered off.The solid was chromatographed to give2-methoxy-3',4-[2,6-pyridinediylbis(oxy)]benzonitrile; NMR (CDCl₃) 7.75(t,1), 7.2-7.5 (m,6), 7.1 (d,1), 6.7 (d,1), 6.65 (d,1), 3.8 (s,3) ppm.

B. In a similar manner, the following compounds were made:

3,3'-bis(methoxy)-4,4'-[2,6-pyridinediylbis(oxy)]bis(benzonitrile); NMR(CDCl₃) 7.75 (t,1), 7.2 (d,2), 7.1 (m,4), 6.65 (d,2), 3.75 (s,6) ppm;

3-[(3,5-difluoro-6-(3-ethylamino-4-methylphenoxy)-4-methylpyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.3 (m,4), 6.95 (d,1), 6.25 (m,2), 3.45 (br s,1), 3.1 (q,2),2.4 (s,3), 2.1 (s,3), 1.3 (t,3) ppm;

3,4'-[2,6-pyridinediylbis(oxy)]bis(benzonitrile); NMR (CDCl₃) 7.8 (t,1),7.6 (d,2), 7.2-7.5 (m,4), 7.14 (d,2), 6.7 (d,2) ppm;

3-[(6-[(3-cyanophenyl)amino]-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.65 (m,2), 7.5 (m,2), 7.2-7.4 (m,4), 2.4 (s,3) ppm;

3-[6-(3-cyanophenyl)amino-3,5-difluoro-4-methylpyridin-2-yl(methylamino)]benzonitrile;NMR (CDCl₃) 7.1-7.5 (m,9), 3.4 (s,3), 2.3 (s,3) ppm;

3-[(3,5-difluoro-4-methyl-6-(pyridin-3-yloxy)pyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 8.4 (m,2), 7.35 (m,4), 7.25 (m,4), 2.4 (s,3) ppm;

3-[(3,5-difluoro-4-methyl-6-phenoxypyridin-2-yl)oxy]benzonitrile; NMR(CDCl₃) 7.25-7.5 (m,6), 7.2 (t, l), 7.0 (d,2), 2.4 (s,3) ppm;

3-[3,5-difluoro-6-(4-dimethylaminophenoxy)-4-methylpyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.25-7.5 (m,4), 6.95 (d,2), 6.65 (d,2), 2.95 (s,6), 2.4(s,3) ppm;

3-[(6-(3,5-difluoro-6-(3-(1H-imidazol-1-yl)phenoxy)-4-methylpyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.75 (s,1), 7.4 (t,1), 7.1-7.3 (m,7), 7.03 (m,2), 2.4 (s,3)ppm;

3-[3,5-difluoro-4-methyl-6-(3-nitrophenoxy)pyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 8.03 (d,1), 7.85 (s,1), 7.5 (t,1), 7.4 (m,3), 7.3 (m,2), 2.4(s,3) ppm;

3-[(6-(3-aminophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.35 (m,4), 7.05 (t,1), 6.45 (d,1), 6.35 (m,2), 2.4 (s,3)ppm;

N-[3-((6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy)phenoxy]acetamide;NMR (CDCl₃) 7.55 (m,2), 7.2-7.4 (m,5), 7.0 (d,1), 6.75 (d,1), 2.4 (s,3),2.2 (s,3) ppm;

3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-methylpyridin-2-yl)oxy]benzonitrile;

3-[3,5-difluoro-6-(3-(2-(dimethylamino)ethyl)phetioxy)-4-methylpyridin-2-yl)oxy]benzonitrile;

1-[3-((6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy)phenyl]urea;

3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzoicacid, ethyl ester;

3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-N,N-dimethylbenzenecarboxamide;

3-[(3,5-difluoro-6-(3-ethylaminophenoxy)-4-methylpyridin-2-yl)oxy]benzonitrile;

3-[(6-(3-diethylaminophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzonitrile;

3-[(3,5-difluoro-4-methyl-6-(3-phenylaminophenoxy)pyridin-2-yl)oxy]benzonitrile;

3-[(6-(3-chlorophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.4 (m,2), 7.2-7.33 (m,3), 7.13 (ddd,1), 7.0 (t,1), 6.91(ddd,1), 2.4 (s,3) ppm;

3-[(3,5-difluoro-4-methyl-6-(3-trifluoromethylphenoxy)pyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.42 (m,3), 7.33 (t,1), 7.15-7.3 (m,4), 2.4 (s,3) ppm;

3-[(3,5-difluoro-6-(3-methoxyphenoxy)-4-methylpyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.25-7.42 (m,5), 6.72 (ddd,1), 6.6 (m,1), 6.58 (m,1), 3.8(s,3), 2.4 (s,3) ppm;

3-[3,5-difluoro-6-(3-fluorophenoxy)-4-methylpyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.35-7.45 (m,2), 7.2-7.33, (m,3), 6;.85 (m,2), 6.73 (dt,1),2.4 (s,3) ppm;

3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-methylpyridin-2-yl)oxy]-4-methylbenzonitrile;NMR (CDCl₃) 7.28 (m,1), 7.26 (s,1), 7.2 (m,2), 7.12 (t,1), 6.48 (dd,1),6.28 (m,2), 2.88 (s,6), 2.38 (s,3), 2.21 (s,3) ppm;

4-amino-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-methylpyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.2 (m,3), 6.66 (d,1), 6.54 (d,1), 6.35 (m,2), 4.28 (s,2),2.91 (s,6), 2.37 (s,3) ppm;

3-[(6-(5-cyano-2-methoxyphenoxy)pyridin-2-yl)oxy]-N,N-dimethiylbenzamide;NMR (CDCl₃) 7.7 (t,1), 7.4 (dd,1), 7.3 (d,1), 7.27 (d,1), 7.15 (dt,1),7.0 (m,2), 6.9 (d,1), 6.66 (d,1), 6.57 (d,1), 3.8 (s,3), 3.1 (s,3), 2.9(s,3) ppm;

3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-5-hydroxybenzoicacid, ethyl ester; NMR (CDCl₃) 7.3 (m,6), 6.7 (s,1), 4.3 (q,2), 2.4(s,3), 1.5 (t,3) ppm;

3-[(6-(5-cyano-2-mnethoxyphenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-5-hydroxybenzoicacid; NMR (CDCl₃) 7.4 (d,1), 7.3 (m,2), 7.1 (s,1), 6.8 (d,1), 6.6 9s,1),5.6 (s,1), 4.4 (q,2), 3.8 (s,3), 2.4 (s,3), 1.4 (t,3) ppm;

2-(3-cyanophenoxy)-6-(5-cyano-2-(benzyloxy)phenoxy)pyridine-4-carboxylicacid, ethyl ester; NMR (CDCl₃) 7.62-7.02 (m,12), 5.16 (s,2H), 4.42(q,2), 1.41 (t,3) ppm;

N-[2-(5-cyano-2-methoxyphenoxy)-6-(3-dimethylaminocarbonylphenoxy)-3,5-difluoropyridin-4-yl]-N-methylglycine,ethyl ester;

N-[2-(5-cyanophenoxy)-6-(3-dimethylaminophenoxy)-3,5-difluoropyridin-4-yl]-N-methylglycine,ethyl ester;

3-[(6-(5-cyano-2-benzyloxyphenoxy)-3,5difluoro-4-(morpholin-1-yl)pyridin-2-yl)oxy]-N, N-dimethylbenzamide;

2-(5-cyano-2-methoxyphenoxy)-6-(3-dimethylaminocarbonylphenoxy)pyridine-4-carboxylicacid, methyl ester; NMR (CDCl₃) 7.2 (m,9), 3.92 (s,3), 3.70 (s,3), 3.10(s,3), 2.88 (s,3) ppm;

2-(5-cyano-2-methoxyphenoxy)-6-(3-dimethylaminocarbonylphenoxy)-N,N-dimethylpyridine-4-carboxamide;NMR (CDCl₃) 7.1 (m,7), 6.55 (s,1), 6.48 (s,1), 3.65 (s,3), 2.95 (m,12)ppm;

2-(3-cyanophenoxy)-6-(3-dimethylaminocarbonylphenoxy)-N,N-dimethylpyridine-4-carboxamide;NMR (CDCl₃) 7.16 (m,8), 6.57 (s,1), 6.53 (s,1), 2.95 (m,12) ppm; and

4-[(2-(3-aminophenoxy)-6-(5-cyano-2-phenylmethoxyphenoxy)-3,5-difluoropyridin-4-yl)oxy]-3-methoxybenzoicacid, ethyl ester.

PREPARATION 10 2,6-Bis(3-cyanophenoxy)-N-methylpyridine-4-carboxamide

A. To 2,6-bis(3-cyanophenoxy)pyridine-4-carboxylic acid, ethyl ester(1.6 g, 4.0 mmol) in tetrahydrofuran/water (50 mL, 1/1) was addedlithium hydroxide (0.85 g, 20 mmol). After stirring for 1.5 hours thereaction was partitioned with 1 M HCl and ethyl acetate. The organiclayer was separated, dried (MgSO₄), and the solvent was removed invacuo. The residue was dissolved in methylene chloride (50 mL) andthionyl chloride (2.4 g, 20 mmol) was added. After stirring for 2 hoursthe solvent was removed in vacuo. The residue was dissolved in methylenechloride/water (30/10 mL) and methylamine hydrochloride (0.090 g, 1.3mmol) and potassium carbonate (0.46 g, 3.3 mmol) were added. The organiclayer was separated, washed with brine, dried (MgSO₄), and the solventremoved in vacuo to give2,6-bis(3-cyanophenoxy)-N-methylpyridine-4-carboxamide; NMR (CDCl₃) 7.5(m,4), 7.3 (m,4), 7.0 (s,2), 6.25 (br s,1), 3.1 (d,3) ppm.

B. In a similar manner, the following compounds were made:

2,6-bis(3-cyanophenoxy)-N-methylpyridine-3-carboxamide; NMR (CDCl₃) 7.8(d,1), 7.4-7.6 (m,5), 7.1-7.3 (m,4), 6.8 (d,1), 3.1 (d,3) ppm;

N-[[12,6-bis(3-cyanophenoxy)pyridin-3-yl]oxomethyl]glycine, ethyl ester;NMR (CDCl₃) 8.65 (d,1), 8.1 (t,1), 7.2-7.6 (m,8), 6.8 (d,1), 4.3 (m,4),1.3 (t,3) ppm; and

2,6-bis(3-cyanophenoxy)-N,N-dimethylpyridine-4-carboxamide; NMR (CDCl₃)7.85 (d,1), 7.45 (m,4), 7.25 (m,4), 6.75 (d,1), 3.2 (s,3), 3.1 (s,3)ppm.

PREPARATION 113-[(6-(3-Cyanophenyl)methylamino-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzonitrile

A. To3-[6-(3-cyanophenyl)amino-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzonitrile(0.10 g, 0.28 mmol) in acetonitrile (10 mL) was added iodomethane (0.20g, 1.4 mmol) and sodium hydride (0.055 g, 1.4 mmol). After stirring for18 hours the reaction was partitioned with water and ethyl acetate. Theorganic layer was separated, dried (Na₂ SO₄), and the solvent wasremoved in vacuo. Chromatography of the residue on silica gel with ethylacetate/hexane (1/3) as eluent gave3-[(6-(3-cyanophenyl)-methylamino-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzonitrile;NMR (CDCl₃) 7.4 (m,5), 7.25 (m,1), 7.1 (m,2), 3.25 (s,3), 2.3 (s,3) ppm.

B. In a similar manner, the following compounds were made:

3-(4-methyl-3,5,6-trifluoropyridin-2-yl)methylaminobenzonitrile; NMR(CDCl₃) 7.35 (t,1), 7.3 (m,1), 7.2 (m,2), 3.4 (s,3), 2.3 (s,3) ppm; and

3,3'-[3,5-difluoro-4-methyl-2,6-pyridinediylbis(methylamino)]bis(benzonitrile);NMR (CDCl₃) 7.1-7.5 (m,8), 3.4 (s,6), 2.3 (s,3) ppm.

PREPARATION 123-[(6-(3-Cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-5-methoxybenzoicAcid, Ethyl Ester

A. To acetonitrile (5 mL) was added3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-5-hydroxybenzoicacid, ethyl ester (0.20 g, 0.47 mmol), cesium carbonate (0.31 g, 0.94mmol), and iodomethane (0.13 g, 0.94 mmol). After stirring for 15 hoursthe mixture was partitioned with ethyl acetate and water. The organiclayer was dried (MgSO₄) and the solvent was removed in vacuo to give3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methyl-pyridin-2-yl)oxy]-5-methoxybenzoicacid, ethyl ester; NMR (CDCl₃) 7.3 (m,6), 6.8 (s,1), 4.4 (q,2), 3.8(s,3), 2.4 (s,3), 1.4 (s,3) ppm.

B. In a similar manner, the following compound was made:

3-[(6-(5-cyano-2-methoxyphenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-5-methoxybenzoicacid, ethyl ester; NMR (CDCl₃) 7.4 (d,1), 7.3 (m,2), 7.1 (s,1), 6.8(d,1), 6.6 (s,1), 4.4 (q,2), 3.8 (s,3), 3.7 (s,3), 2.4 (s,3), 1.4 (t,3)ppm.

PREPARATION 135-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzene-1,3-dicarboxylicacid

A. To5-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzene-1,3-dicarboxylicacid, diethyl ester (0.97 g, 2.0 mmol) in tetrahydrofuran/water (20 mL,1/1) was added lithium hydroxide (0.42 g, 10 mmol). After heating at 60°C. for 90 minutes, the material was partitioned between ethyl acetateand 2 N HCl. The organic layer was separated, dried (MgSO₄), and thesolvent removed in vacuo to give5-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methyl-pyridin-2-yl)oxy]benzene-1,3-dicarboxylicacid; NMR (DMSO) 8.25 (s,1), 7.85 (s,2), 7.4-7.7 (m,3), 7.3 (m,3), 2.4(s,3) ppm.

B. In a similar manner, the following compounds were made:

3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-2,3-dimethoxybenzenecarboxylicacid; NMR (DMSO-d₆) 7.95 (s,1), 7.1-7.7 (m,5), 3.85 (s,3), 3.6 (s,3),2.4 (s,3) ppm;

3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-5-methoxybenzoicacid; and

3-[(6-(5-cyano-2-methoxyphenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-5-methoxybenzoicacid

PREPARATION 143-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-N,N-dimethyl-4-methoxybenzamide

A. To3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-4-methoxybenzoicacid (0.47 g, 1.1 mmol) in tetrahydroturan (12 mL) was added1,1'-carbonyldiimidazole (0.22 g, 1.4 mmol) and stirred at ambienttemperature for 3 hours. Then dimethylamine (aq, 0.077 g, 1.7 mmol) wasadded. After stirring for 12 hours the solution was partitioned betweenwater and ethyl acetate. The organic layer was separated, dried (MgSO₄),and the solvent was removed in vacuo. Chromatography on silica gel withethyl acetate/hexane (1/8) as eluent gave3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-N,N-dimethyl-4-methoxybenzamide;NMR (CDCl₃) 6.9-7.4 (m,7), 3.8 (s,3), 3.0 (br,6), 2.4 (s,3) ppm.

B. In a similar manner, the following compounds were made:

3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-N,N-dimethyl-4-methoxybenzamide;NMR (CDCl₃) 7.3 (m,2), 7.2 (m,3), 7.15 (d,1), 6.95 (s,1), 3.05 (br,3),2.85 (br,3), 2.4 (s,3), 2.15 (s,3) ppm;

5-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-N,N,N',N'-tetraethylbenzene-1,3-dicarboxamide;NMR (CDCl₃) 7.9 (s,1), 7.65 (s,2), 7.1-7.5 (m,4), 3.45 (br,4), 3.15(br,4), 2.4 (s,3), 1.25 (br,6), 1.05 (br,6) ppm;

5-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-2,3-dimethoxy-N,N-dimethylbenzamide;NMR (DMSO-d₆) 7.95 (m,1), 7.1-7.7 (m,5), 3.9 (s,3), 3.65 (s,3), 3.4(s,3), 3.15 (s,3), 2.4 (s,3) ppm;

5-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-N,N,N',N'-tetramethylbenzene-1,3-dicarboxamide;NMR (CDCl₃) 7.7 (s,2), 7.1-7.5 (m,5), 3.1 (m,6), 2.9 (s,3), 2.85 (s,3),2.4 (s,3) ppm;

4-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-3-methoxy-N,N-dimethylbenzamide;NMR (CDCl₃) 7.7 (s,1), 7.2-7.4 (m,3), 7.1 (s,1), 7.05 (m,1), 6.95 (d,1),3.8 (s,3), 3.1 (s,3), 3.0 (s,3), 2.4 (s,3) ppm;

1-[3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzoyl]pyrrolidine;NMR (CDCl₃) 7.2-7.5 (m,6), 7.2 (s,1), 7.1 (d,1), 3.65 (m,2), 3.3 (m,2),2.4 (s,3), 1.8-2.1 (m,4) ppm;

1-[3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzoyl]morpholine;

4-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-N,N-dimethyl-benzamide;NMR (CDCl₃) 7.2-7.6 (m,6), 7.05 (d,2), 3.2 (br,3), 3.0 (br,3), 2.4 (s,3)ppm;

3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-N-methylbenzenecarboxamide;

1-[3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzoyl]-4-ethylpiperazine

1-[3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzoyl]piperidine;

3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-N-methyl-N-(phenylmethyl)benzamide;

3-[6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-N-methyl-N-[2-(pyridin-2-yl)ethyl]benzamide;

3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-N-ethyl-N-methylbenzamide;

3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-N,N-diethylbenzamide;

N-[3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzoyl]-.beta.-alanine,ethyl ester;

3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-N,N-dimethyl-5-methoxybenzamide;NMR (CDCl₃) 7.4 (m,2), 7.3 (m,2), 6.7 (s,1), 6.6 (s,2), 3.8 (s,3), 3.0(s,3), 2.8 (s,3), 2.4 (s,3) ppm; and

3-[(6-(5-cyano-2-methoxyphenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-N,N-dimethyl-5-methoxybenzamide;NMR (CDCl,3) 7.4 (d,1), 7.3 (s,1), 6.9 (d,1), 6.6 (d,1), 6.5 (d,1), 3.8(s,6), 3.1 (s,3), 2.9 (s,3), 2.4 (s,3) ppm.

PREPARATION 15 3,3'-[3-Amino-2,6-pyridinediylbis(oxy)]bis(benzonitrile)

A. To 3,3'-[3-nitro-2,6-pyridinediylbis(oxy)]bis(benzonitrile)(18.5 g,50 mmol) dissolved in ethanol/ethyl acetate (500 mL, 2/3) was added 10%palladium on carbon (1.8 g). After subjecting the mixture to hydrogen at15 psi for 2 hours, the reaction was suction filtered through celite.The solvent was removed in vacuo to give3,3'-[3-amino-2,6-pyridinediylbis(oxy)]-bis(benzonitrile); NMR (CDCl₃)7.5 (m,7), 7.2 (m,2), 6.6 (d,1), 3.8 (br,2) ppm.

PREPARATION 16 N-[2,6-Bis(3-cyanophenoxy)pyridin-3-yl]benzamide

A. To 3,3'-[3-amino-2,6-pyridinediylbis(oxy)]bis(benzonitrile) (1.0 g,2.9 mmol) dissolved in acetonitrile (50 mL) was added benzoyl chloride(0.50 g, 3.5 mmol) and triethylamine (0.45 g, 0.60 mmol). After stirringfor 3 hours, the reaction was partitioned between ether and water. Theorganic layer was separated, washed with water, saturated aqueous sodiumbicarbonate, and brine, dried (MgSO₄), and the solvent was removed invacuo. Chromatography on silica gel with ethyl acetate/hexane (1/3)aseluentgaveN-[2,6-bis(3-cyanophenoxy)pyridin-3-yl]benzamide; NMR(CDCl₃)8.95 (d,1), 8.25 (s,1), 7.9 (d,1), 7.2-7.7 (m,12), 6.8 (d,1) ppm.

B. In a similar manner, the following compounds were made:

N-[2,6-bis(3-cyanophenoxy)pyridin-3-yl]acetamide; NMR (CDCl₃) 8.65(d,1), 7.6 (s,1), 7.1-7.6 (m,8), 6.7 (d,1), 2.3 (s,3) ppm;

N-[[(2,6-bis(3-cyanophenoxy pyridin-3-yl)amino]carboxy]glycine, ethylester; NMR (CDCl₃) 8.5 (d,1), 7.2-7.5 (m,8), 7.15 (s,1), 6.6 (d,1), 5.7(m,1), 4.2 (q,2), 4.1 (m,2), 1.25 (d,3) ppm;

N-[2,6-bis(3-cyanophenoxy)pyridin-3-yl]methanesulfonamide; NMR (CDCl₃)8.0 (d,1), 7.45 (m,4), 7.25 (m,4), 6.75 (d,1), 6.6 (s,1), 3.1 (s,3) ppm;and

N-[3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]phenyl]methanesulfonamide;NMR (CDCl₃) 8.8 (d,1), 7.65 (m,2), 7.35 (m,4), 7.05 (m,2), 2.95 (s,3),2.3 (s,3) ppm.

PREPARATION 17 N-[2,6-Bis(3-cyanophenoxy)pyridin-3-yl]-N'-phenylurea

A. To 3,3'-[3-amino-2,6-pyridinediylbis(oxy)]bis(benzonitrile) (3.0 g,8.7 mmol) dissolved in acetonitrile (100 mL) was added phenyl isocyanate(1.1 g, 9.5 mmol). After refluxing for 4 hours, the reaction waspartitioned between ether and water. The organic layer was separated,washed with water, saturated aqueous sodium bicarbonate, and brine,dried (MgSO₄), and the solvent was removed in vacuo. Chromatography onsilica gel with ethyl acetate/hexane (1/4) as eluent gave material whichwas crystallized from ethyl acetate/hexane to giveN-[2,6-bis(3-cyano-phenoxy)pyridin-3-yl]-N'-phenylurea; NMR (CDCl₃) 8.65(d,1), 7.4 (m,8), 7.1-7.3 (m,6), 6.8 (s,1), 6.7 (d,1) ppm.

B. In a similar manner, the following compound was made:

N-[2,6-bis(3-cyanophenoxy)pyridin-3-yl]-N'-methylurea; NMR (CDCl₃) 8.65(d,1), 7.5 (m,4), 7.25 (m,4), 6.8 (s,1), 6.7 (d,1), 2.9 (d,3) ppm.

PREPARATION 183-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzenepropionicAcid, Methyl Ester

To3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzene-propionicacid(0.50g, 1.2 mmol) in methylene chloride (20 mL) was added methyl iodide (0.26g, 1.8 mmol) and diazabicycloundecane (2.8 g, 1.8 mmol). After stirringfor 15 hours, the solution was concentrated in vacuo and chromatographedon silica gel with ethyl acetate/hexane (1/4) to give3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzenepropionicacid, methyl ester; NMR (CDCl₃) 7.3 (m,5), 7.05 (d,1), 6.85 (m,2), 3.68(s,3), 2.9 (t,2), 2.55 (t,2), 2.4 (s,3) ppm.

PREPARATION 19 4,4'-[1,3-Phenylenebis(oxy)]benzonitrile

To DMSO (6 mL) was added resorcinol (1.1 g, 10 mmol),4-fluorobenzonitrile (2.4 g, 20 mmol) and potassium carbonate (2.4 g, 17mmol). After heating in an oil bath at 100° C. for 16 hours the reactionmixture was partitioned with water and ethyl acetate. The organic layerwas separated, washed with 1 N sodium hydroxide, water, brine, dried(sodium sulfate) and concentrated in vacuo. Chromatography on silica gelwith methylene chloride/hexane (20/1) as eluent gave4,4'-[1,3-phenylenebis(oxy)]benzonitrile; NMR (CDCl₃) 7.64 (d,4), 7.43(t,1), 7.06 (d,4), 6.82 (dd,2), 6.80 (t,1) ppm.

PREPARATION 204-[(2-(3-(Guanidino)phenoxy)-6-(5-cyano-2-benzyloxyphenoxy)-3,5-difluoropyridin-4-yl)oxy]-3-methoxybenzoicAcid, Ethyl Ester.

To ethanol (15 mL) was added4-[[2-(3-aminophenoxy)-6-(5-cyano-2-phenylmethoxyphenoxy)-3,5-difluoropyridin-4-yl]oxy]-3-methoxybenzoicacid, ethyl ester (0.50 g, 0.80 mmol), cyanamide (0.60 g, 14 mmol), and6 M hydrochloric acid (0.7 mL). After refluxing for 19 hours, cyanamide(0.60 g, 14 mmol) and 6 M hydrochloric acid (0.7 mL) was added andrefluxing was continued for 4 hours. The reaction mixture wasconcentrated in vacuo and purified by HPLC to give4-[[2-[3-(guanidino)phenoxy)-6-(5-cyano-2-benzyloxyphenoxy)-3,5-difluoropyridin-4-yl)oxy]-3-methoxybenzoicacid, ethyl ester.

EXAMPLE 1 3,3'-[2,6-Pyridinediylbis(oxy)]bis(benzamidine),Dihydrochloride

A. To 3,3'-[2,6-pyridinylbis(oxy)]bis(benzonitrile) (0.2 g, 0.7 mmol)slurried in ethanol (6 mL) cooled in a dry ice/isopropanol bath wasbubbled HCl (g). After the solution was saturated the reaction flask wassealed and allowed to warm to ambient temperature and stir for 18 hours.The solvent was removed in vacuo and the residue was triturated withether. The ether was removed by decantation and the residue wasdissolved in ethanol (6 mL). The solution was cooled in a dryice/isopropanol bath and ammonia (g) was bubbled in. The reaction flaskwas sealed and heated to 50° C. for 2 hours. The solvent was removed invacuo and the residue was recrystallized from 5 M HCl to give3,3'-[2,6-pyridinediylbis(oxy)]bis(benzamidine), dihydrochloride as asolid; m.p. 160° C. (decom); NMR (DMSO-d₆) 9.45 (s,4), 9.3 (s,4), 8.02(t,1), 7.4-7.8 (m,8), 6.90 (d,2) ppm.

B. In a similar manner, the following compounds were made:

4,4'-[2,6-pyridinediylbis(oxy)]bis(benzamidine), dihydrochloride; NMR(DMSO-d₆) 9.4 (s,4), 9.2 (s,4), 8.1 (t,1), 7.95 (d,4), 7.40 (d,4), 6.96(d,2) ppm;

3,3'-bis(methoxy)-4,4'-[2,6-pyridinediylbis(oxy)]bis(benzamidine),dihydrochloride; NMR (DMSO-d₆) 9.5 (br s,4), 9.2 (br s,4), 7.9 (t,1),7.7 (s,2), 7.5 (d,2), 7.3 (d,2), 6.7 (d,2), 3.85 (s,6) ppm;

4-[(6-(3-amidinophenoxy)pyridin-2-yl)oxy]-3-methoxybenzamidine,dihydrochloride; NMR (DMSO-d₆) 9.7 (s,2), 9.55 (s,2), 9.4 (br s,4), 7.95(t,1), 7.75 (s,1), 7.3-7.7 (m,6), 6.85 (d,1), 6.75 (d,1), 3.9 (s,3) ppm;

3-[(3,5-difluoro-6-(3-ethylamino-4-methylphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,dihydrochloride; NMR (DMSO-d₆) 9.4 (s,2), 9.2 (s,2), 7.6 (m,2), 7.55(t,1), 7.45 (m,1), 7.3 (m,2), 7.15 (dd,1), 3.2 (q,2), 2.4 (s,3), 2.35(s,3), 1.2 (t,3) ppm;

3,3'-[3-trifluoromethyl-2,6-pyridinediylbis(oxy)]bis(benzamidine),dihydrochloride; NMR (DMSO-d₆) 9.4 (s,4), 9.2 (s,4), 8.3 (d,1), 7.7(m,4), 7.6 (d,4), 7.0 (m,1) ppm;

3,4'-(2,6-pyridinediylbis(oxy)]bis(benzamidine), dihydrochloride; NMR(DMSO-d₆) 9.4 (br s,8), 8.1 (t,1), 7.9 (d,2), 7.5-7.8 (m,4), 7.40 (d,2),6.95 (m,2) ppm;

3,3'-[3-methylaminocarbonylamino-2,6-pyridinediylbis(oxy)]bis(benzamidine),dihydrochloride; m.p. 205-206° C.;

4-methoxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-carboxypyridin-2-yl)oxy]benzamidine,hydrochloride; NMR (DMSO-d₆) 9.2 (s,2), 9.0 (s,2), 7.9 (t,1), 7.78(dd,1), 7.68 (m,1), 7.36 (t,1), 7.26 (d,1), 7.15 (d,1), 7.05 (m,1), 7.02(m,1), 6.75 (d,1), 6.7 (d,1), 3.8 (s,3), 2.95(s,3), 2.8 (s,3) ppm;

4-methoxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-methyl-piperazinoyl)pyridin-2-yl)oxy]benzamidine,dihydrochloride;

3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-((methyl)(ethoxycarbonylmethyl)amino)pyridin-2-yl)oxy]benzamidine, ethyl ester, hydrochloride; NMR (DMSO-d₆)9.3 (s,2), 9.2 (s,2), 7.5 (m,4), 7.2 (t,1), 6.7 (m,2), 6.5 (d,1), 4.2(s,2), 3.2 (s,3), 2.9 (s,6) ppm;

4-methoxy-3-[(6-(3-dimethylaminocarbonylphenoxy)-4-(dimethylaminocarbonyl)pyridin-2-yl)oxy]benzamidine,hydrochloride;

4-methoxy-3-[(6-(3-dimethylaminocarbonylphenoxy)-4-(aminocarbonyl)pyridin-2-yl)oxy]benzamidine,hydrochloride; and

4-methoxy-3-[(6-(3-dimethylaminocarbonylphenoxy)-4-(ethoxycarbonyl)pyridin-2-yl)oxy]benzamidine,hydrochloride.

C. In a similar manner, reaction of3,3'-[3,5-difluoro-4-methyl-2,6-pyridinediylbis(oxy)]bis(benzonitrile)gave3,3'-[3,5-difluoro-4-methyl-2,6-pyridinediylbis(oxy)]bis(benzamidine);which was purified by HPLC on a C18 Dynamax column with a 20-80%acetonitrile in water gradient with 0.1% trifluoroacetic acid to givethe compound as a pure trifluoroacetic acid salt; m.p. >210° C.; NMR(DMSO-d₆) 9.3 (br s,8), 7.6 (m,4), 7.54 (m,4), 2.4 (m,3) ppm.

D. In a similar manner, the following compounds were made:

3,3'-(3,5-dichloro-2,6-pyridinediylbis(oxy))bis(benzamidine),trifluoroacetic acid salt; NMR (DMSO-d₆) 9.2 (br s,8), 8.6 (s,1),7.4-7.7 (m,8) ppm;

4,4'-(3,5-dichloro-2,6-pyridinediylbis(oxy))bis(benzamidine),trifluoroacetic acid salt; NMR (DMSO-d₆) 9.25 (s,4), 9.0 (s,4), 8.58(s,1), 7.8 (d,4) 7.4 (d,4) ppm;

3,3'-(4-ethoxycarbonyl-2,6-pyridinediylbis(oxy))bis(benzamidine),trifluoroacetic acid salt; NMR (DMSO-d₆) 9.55 (br s,4), 9.4 (br s,4),7.65 (m,4), 7.6 (m,4), 7.2 (s,2), 4.4 (q,2), 1.4 (t,3) ppm;

3,3'-(3-ethoxycarbonyl-2,6-pyridinediylbis(oxy))bis(benzamidine),trifluoroacetic acid salt; NMR (DMSO-d₆) 9.35 (br s,4), 9.1 (br s,4),8.4 (d,1), 7.6 (m,4), 7.5 (m,4), 6.9 (d,1), 4.3 (q,2), 1.3 (t,3) ppm;

3,3'-(3,5-difluoro-2,6-pyridinediylbis(oxy))bis(benzamidine),trifluoroacetic acid salt; NMR (DMSO-d₆) 9.55 (br s,4), 9.4 (br s,4),8.5 (t,1), 7.7 (m,4), 7.55 (m,4) ppm;

3,3'-(4-methylaminocarbonyl-2,6-pyridinediylbis(oxy))bis(benzamidine),trifluoroacetic acid salt; NMR (DMSO-d₆) 9.35 (br s,4), 9.2 (br s,4),8.85 (m,1), 7.5-7.7 (m,8), 7.2 (s,2), 2.9 (d,3) ppm;

3,3'-(3-methylaminocarbonyl-2,6-pyridinediylbis(oxy))bis(benzamidine),trifluoroacetic acid salt; NMR (DMSO-d₆) 9.6 (m,4), 9.4 (br s,4), 8.65(d,1), 8.5 (m,1), 7.7-8.0 (m,8), 7.2 (d,1), 2.85 (d,3) ppm.

3,3'-(3-dimethylaminocarbonyl-2,6-pyridinediylbis(oxy))bis(benzamidine),trifluoroacetic acid salt; m.p. 180-183° C.;

3,3'-(3-((aminocarbonyl)methylaminocarbonyl)-2,6-pyridinediylbis(oxy))bis(benzamidine),trifluoroacetic acid salt; NMR (DMSO-d₆) 9.3 (s,2), 9.25 (s,2), 9.05(s,4), 8.5 (d,1), 7.4-7.7 (m,11), 6.85 (d,1), 4.0 (d,2) ppm;

3-[(3,5-difluoro-6-(5-dimethylamino-2-methylphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.25 (s,2), 9.1 (s,2), 7.4-7.6(m,3), 7.2-7.4 (m,4), 3.1 (s,6), 2.4 (s,3), 2.1 (s,3) ppm;

3-[(3,5-difluoro-6-(3-dimethylamino-2-methylphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.25 (s,2), 9.1 (s,2), 7.5-7.7(m,4), 7.4 (m,1), 7.3 (m,1), 7.2 (d,1), 3.1 (s,6), 2.4 (s,3), 2.3 (s,3)ppm;

3-[(3,5-difluoro-6-((3-amidinophenyl)methylamino)-4-methylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.35 (s,2), 9.3 (s,2), 9.15(s,2), 9.05 (s,2), 7.6 (m,4), 7.4 (m,3), 7.25 (m,1), 7.2 (d,1), 3.25(s,3), 2.3 (s,3) ppm;

3-[(3,5-difluoro-6-[(3-amidinophenyl)amino]-4-methylpyridin-2-yl)oxy]benzamidine;trifluoroacetic acid salt; NMR (DMSO-d₆) 9.35 (s,2), 9.2 (s,4), 8.95(s,2), 7.5-7.8 (m,6), 7.25 (m,2), 2.35 (s,3) ppm;

3,3'-(3,5-difluoro-4-methoxy-2,6-pyridinediylbis(oxy))bis(benzamidine),trifluoroacetic acid salt; NMR (DMSO-d₆) 9.3 (br s,4), 9.2 (br s,4), 7.6(m,4), 7.5 (m,4), 4.3 (s,3), 2.3 (m,3) ppm;

3,3'-(3,5-difluoro-4-methyl-2,6-pyridinediylbis(methylamino))bis(benzamidine),trifluoroacetic acid salt; m.p. 115-120° C.;

3-[(6-(2-methoxy-5-dimethylaminocarbonylphenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.3 (s,2), 9.1 (s,2), 7.5(m,3), 7.3 (d,1), 7.2 (m,2), 7.1 (d,1), 3.75 (s,3), 2.9 (br,6), 2.4(s,3) ppm;

3-[(6-(2,3-dimethoxy-5-ethoxycarbonylphenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; m.p. 200-202° C.;

3-[(6-(2-methyl-5-dimethylaminocarbonylphenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.3 (s,2), 9.15 (s,2), 7.5(m,3), 7.45 (d,1), 7.3 (d,1), 7.1 (m,2), 2.95 (s,3), 2.75 (s,3), 2.4(s,3), 2.15 (s,3) ppm;

3-[(6-(3,5-di(diethylaminocarbonyl)phenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.35 (s,2), 9.05 (s,2), 7.6(m,3), 7.45 (m,1), 7.2 (s,2), 7.1 (s,1), 3.45 (br,4), 3.15 (br,4), 2.4(s,3) 1.2 (br,6), 1.05 (br,6) ppm;

3-[(6-(2,3-dimethoxy-5-dimethylaminocarbonylphenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.25 (s,2), 9.1 (s,2), 7.95(s,1), 7.4-7.6 (m,4), 7.3 (s,1), 3.9 (s,3), 3.7 (s,3), 2.5 (s,6), 2.4(s,3) ppm;

3-[(6-(3,5-di(dimethylaminocarbonyl)phenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.3 (s,2), 9.05 (s,2), 7.55(m,4), 7.25 (s,2), 7.2 (s,1), 3.0 (s,6), 2.85 (s,6), 2.4 (s,3) ppm;

3-[(6-(2-methoxy-4-dimethylaminocarbonylphenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.3 (s,2), 9.15 (s,2), 7.5(m,3), 7.35 (m,1), 7.15 (d,1), 7.1 (s,1), 6.9 (d,1), 3.7 (s,3), 3.05(br,3), 2.9 (br3), 2.4 (s,3) ppm;

3,3'-(4-phenylcarbonylamino-2,6-pyridinediylbis(oxy))bis(benzamidine),trifluoroacetic acid salt; m.p. 269-271° C.;

3,3'-(3-phenylaminocarbonylamino-2,6-pyridinediylbis(oxy))bis(benzamidine),trifluoroacetic acid salt; m.p. 159-160° C.;

3,3'-(3-(aminocarbonylmethylaminocarbonylamino-2,6-pyridinediylbis(oxy))bis(benzamidine),trifluoroacetic acid salt; m.p. 129-130° C.;

3,3'-[3-amino-2,6-pyridinediylbis(oxy)]bis(benzamidine), trifluoroaceticacid salt; NMR (DMSO-d₆) 9.5 (br,4), 9.2 (br,4), 7.3-7.7 (m,9), 6.8(d,1) ppm;

3,3'-[3-methylsulfonylamino-2,6-pyridinediylbis(oxy)]bis(benzamidine),trifluoroacetic acid salt; NMR (DMSO-d₆) 9.6 (s,1), 9.4 (m,8), 8.4(d,1), 7.95 (d,1), 7.5-7.7 (m,8), 6.9 (d,1), 3.1 (s,3) ppm;

3,3'-[3-methylcarbonylamino-2,6-pyridinediylbis(oxy)]bis(benzamidine),2-trifluoroacetic acid salt; NMR (DMSO-d₆) 9.8 (s,1), 9.3 (m,4), 9.25(m,4), 8.4 (d,1), 7.4-7.7 (m,8), 6.9 (d,1), 2.15 (s,3) ppm;

3-[(6-(3-aminophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.35 (s,2), 9.2 (s,2), 7.6(m,3), 7.55 (m,1), 7.0 (t,1), 6.45 (d,1), 6.35 (m,2), 2.4 (s,3) ppm;

3-[(3,5-difluoro-6-[3-[2-(1H-imidazol-1-yl)-1-oxoethyl]phenoxy]-4-methylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.4 (s,2), 9.3 (s,2), 9.0(s,1), 7.4-7.9 (m,10), 6.0 (s,2), 2.4 (s,3) ppm;

3-[6-(3-(2-(dimethylaminocarbonyl)ethyl)phenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.3 (s,2), 9.25 (s,2), 7.6(m,4), 7.2 (t,1), 7.0 (m,2), 6.9 (d,1), 2.9 (s,3), 2.8 (s,3), 2.75(t,2), 2.5 (m,2) 2.4 (s,3) ppm;

3-[(3,5-difluoro-6-[3-(hydroxymethyl)phenoxy]-4-methylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.4 (br,4), 7.6 (m,4), 7.25(t,1), 7.1 (d,1), 7.05 (m,1), 7.0 (d,1), 4.45 (s,2), 2.4 (s,3) ppm;

3-[(6-(3-(dimethylaminocarbonyl)methylphenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.3 (s,4), 7.6 (m,3), 7.55(m,1), 7.2 (t,1), 7.0 (m,2), 3.6 (s,2), 2.95 (s,3), 2.8 (s,3), 2.4 (s,3)ppm;

3-[(6-(3-(amirocarbonyl)methylphenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; m.p. 189-192° C.;

3-[(6-[3-(aminomethyl)phenoxy]-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.3 (br,4), 8.2 (br,3), 7.6(m,3), 7.55 (m,1), 7.35 (t,1), 7.2 (m,2), 7.15 (d,1), 4.0 (m,2), 2.4(s,3) ppm;

3-[(3,5-difluoro-4-methyl-6-[3-(prop-2-oxymethyl)phenoxy]pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.3 (s,2), 9.1 (s,2), 7.6(m,4), 7.2 (t,1), 6.65 (m,3), 4.55 (m,1), 2.4 (s,3), 1.15 (m,6) ppm;

4,4'-[1,3-phenylenebis(oxy)]bis(benzamidine), trifluoroacetic acid salt;NMR (DMSO-d₆) 9.4 (br,4), 9.2 (br,4), 7.96 (d,4), 7.6 (t,1), 7.3 (d,4),7.05 (dd,2), 6.97 (m,1) ppm;

3,3'-[4-nitro-1,3-phenylenebis(oxy)]bis(benzamidine), trifluoroaceticacid salt; NMR (DMSO-d₆) 9.4 (s,4), 9.2 (m,4), 8.25 (d,1), 7.6 (m,8),7.0 (dd,1), 6.9 (m,1) ppm;

3-[(6-(3-methoxy-5-dimethylaminocarbonylphenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.3 (s,2), 9.1 (s,2), 7.6(m,4), 6.8 (s,1), 6.7 (d,2), 3.7 (s,3), 3.0 (s,3), 2.8 (s,3), 2.4 (s,3)ppm;

4-methoxy-3-[(6-(3-methoxy-5-dimethylaminocarbonylphenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.1 (s,2), 9.0 (s,2), 7.8(d,1), 7.7 (s,1), 7.2 (d,1), 6.7 (s,1), 6.6 (s,1), 6.5 (s,1), 3.8 (s,3),3.7 (s,3), 2.9 (s,3), 2.7 (s,3), 2.4 (s,3) ppm;

4-methoxy-3-[(6-(3-(imidazol-1-yl)phenoxy)-4-ethoxycarbonylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.1 (s,2), 8.9 (s,2), 8.0(s,1), 7.6 (m,7), 7.2 (m,4), 4.4 (q,2), 3.7 (s,3), 1.3 (t,3) ppm;

4-methoxy-3-[(6-(3-dimethylaminocarbonylphenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt, NMR (CDCl₃) 9.10 (s,2), 8.94 (s,2), 7.71(d,1), 7.66 (s,1), 7.32 (t,1), 7.25 (d,1), 7.09 (d,1), 7.01 (d,1), 6.95(s,1), 3.77 (s,3), 2.95 (s,3), 2.75 (s,3), 2.37 (s,3);

4-amino-3-[(6-(3-dimethylaminocarbonylphenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (CDCl₃) 8.8 (s,4), 7.71 (d,1), 7.5 (d,1),7.4 (s,1), 7.3 (t,1), 7.1-7.2 (m,2), 7.1 (s,1), 6.6 (d,1), 6.2 (s,2),3.0 (s,3), 2.8 (s,3), 2.4 (s,3) ppm;

4-amino-3-[(6-(3-dimethylaminocarbonylphenoxy)-3,5-difluoro-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (CDCl₃) 8.7 (s,2), 8.5 (s,2), 7.4-7.5(m,2), 7.3 (t,1), 7.1-7.2 (m,3), 6.7 (d,1), 6.2 (br s,2), 5.2 (q,2), 3.0(s,3), 2.8 (s,3) ppm;

4-methoxy-3-[(6-(3-dimethylaminocarbonylphenoxy)-3,5-difluoro-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

3,3'-[2,6-pyrazinediylbis(oxy)]bis(benzamidine), trifluoroacetic acidsalt; NMR (DMSO-d₆) 9.4 (s,8), 8.4 (s,2), 7.6 (m,8) ppm;

3,3'-[2,6-pyrimidinediylbis(oxy)]bis(benzamidine), trifluoroacetic acidsalt; NMR (DMSO-d₆) 9.4 (m,8), 8.6 (d,1), 7.7 (m,8), 7.05 (d,1) ppm;

4-hydroxy-3-[(6-(3-dimethylaminocarbonylphenoxy)-3,5-difluoro-2-methoxypyridin-4-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 11.3 (s,1), 9.1 (m,2), 8.8(s,2), 7.6 (m,2), 7.5 (t,1), 7.2 (m,3), 7.05 (d,1), 3.8 (s,3), 3.0(s,3), 2.9 (s,3) ppm;

4-amino-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-((methyl)(aminocarbonylmethyl)amino)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-amino-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-((methyl)(ethoxycarbonylmethyl)amino)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-amino-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(methyl)(phenyl)aminocarbonylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-methoxy-3-[(6-(3-dimethylaminocarbonylphenoxy)-3,5-difluoro-4-(1,3-difluoroprop-2-oxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

3-[(6-(3-dimethylaminocarbonylphenoxy)-4-dimethylaminocarbonylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.31 (s,2), 9.24 (s,2), 7.35(m,8), 6.81 (s,1), 6.78 (s,1), 2.95 (m,12) ppm;

3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(4-ethoxycarbonyl-2-methoxyphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(4-ethoxycarbonyl-2-(morpholin-4-ylmethyl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; and

3-[(3-(3-amidinophenoxy)phen-1-yl]oxy]benzamidine, trifluoroacetic acidsalt.

EXAMPLE 23-[(6-(3-Amidinophenoxy)-4-carboxypyridin-2-yl)oxy]benzamidine,Dihydrochloride

2,6-Bis(3-amidinophenoxy)pyridine-4-carboxamide (5 g, 11 mmol) wasdissolved in 5 M HCl and heated. The solid that precipitated on coolingwas collected by filtration to give3-[(6-(3-amidinophenoxy)-4-carboxypyridin-2-yl)oxy]benzamidine,dihydrochloride; NMR (DMSO-d₆) 9.4 (br s,4), 9.2 (br s,4), 7.4 (m,4),7.3 (m,4), 7.2 (s,2) ppm.

EXAMPLE 33-[(3,5-Difluoro-4-methyl-6-[(pyridin-3-yl)oxy]pyridin-2-yl)oxy]benzamidine,Acetic Acid Salt

A. In a manner similar to Example 1 above,3-[(3,5-difluoro-4-methyl-6-[(pyridin-3-yl)oxy]pyridin-2-y]oxy]benzonitrilewas reacted with HCl and ammonia (g). The solvent was removed in vacuoand the material was partitioned with methylene chloride and 2 N aqueouspotassium hydroxide. The organic layer was separated, acetic acid added,and the solvent was removed in vacuo. The residue was triturated withether and the resulting solid was filtered to give3-[(3,5-difluoro-4-methyl-6-[(pyridin-3-yl)oxy]pyridin-2-yl)oxy]benzamidine,acetic acid salt; m.p. 213-214° C.

B. In a similar mariner, the following compounds were made:

3-[(3,5-difluoro-4-methyl-6-phenoxypyridin-2-yl)oxy]benzamidine, aceticacid salt; m.p. 122-123° C.;

3-[(3,5-difluoro-6-(4-dimethylaminophenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; m.p. 106-107° C.;

3-[(3,5-difluoro-6-[3-(1H-imidazol-1-yl)phenoxy]-4-methylpyridin-2-yl)oxy]benzamidine, aceticacid salt; NMR (DMSO-d₆) 9.9 (br,4), 8.3 (s,1), 7.8 (s,1), 7.65 (m,6),7.3 (t,1) 7.15 (m,2), 2.4 (s,3) ppm;

3-[(3,5-difluoro-4-methyl-6-(3-nitrophenoxy)pyridin-2-yl)oxy]benzamidine,acetic acid salt; NMR (DMSO-d₆) 10.1 (br,4), 8.05 (m,2), 7.7 (m,2), 7.6(m,2), 7.5 (m,2), 2.45 (s,3) 1.8 (s,3) ppm;

3-[(3,5-difluoro-4-methyl-6-[3-[(methylsulfonyl)amino]phenoxy]pyridin-2-yl)oxy]benzamidine,acetic acid salt; NMR (DMSO-d₆) 10 (br,4), 7.5 (m,3), 7.4 (d,1), 7.15(t,1), 6.85 (d,1), 6.8 (t,1), 6.66 (dd,1), 2.83 (s,3), 2.36 (s,3) 1.74(s,3) ppm;

3-[(3,5-difluoro-6-(3-methylcarbonylaminophenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; NMR (DMSO-d₆) 10.3 (br,4), 10.1 (s,1), 7.4-7.7 (m,5),7.25 (m,2), 6.8 (m,1), 2.4 (s,3), 2.1 (s,3), 1.8 (s,3) ppm;

3-[(3,5-difluoro-6-(4-dimethylaminomethylphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; m.p. 103-105° C.;

3-[(3,5-difluoro-4-methyl-6-(3-(morpholin-4-yl)phenoxy)pyridin-2-yl)oxy]benzamidine,acetic acid salt; m.p. 194-196° C.;

3-[(3,5-difluoro-4-methyl-6-(3-(1-pyrrolidinoyl)phenoxy)pyridin-2-yl)oxy]benzamidine,acetic acid salt; m.p. 162-164° C.;

3-[(3,5-difluoro-4-methyl-6-(3-(4-morpholinoyl)phenoxy)pyridin-2-yl)oxy]benzamidine,acetic acid salt; m.p. 123-126° C.;

3-[(3,5-difluoro-4-methyl-6-(3-dimethylaminocarbonylphenoxy)pyridin-2-yl)oxy]benzamidine,acetic acid salt; m.p. 198-200° C.;

3-[(3,5-difluoro-4-methyl-6-(3-(carboxy)(hydroxy)methylphenoxy)pyridin-2-yl)oxy]benzamidine,acetic acid salt; NMR (DMSO-d₆) 10 (br,4), 7.4-7.7 (m,6), 7.25 (m,3),7.15 (m,1), 7.05 (m,1), 4.82 (s,1), 2.4 (s,3), 1.8 (s,3) ppm;

3-[(3,5-difluoro-4-methyl-6-[3-(1-oxoethyl)]phenoxy]pyridin-2-yl)oxy]benzamidine,acetic acid salt; NMR (DMSO-d₆) 10.2 (br,4), 7.75 (m,1), 7.65 (m,1),7.4-7.6 (m,6), 2.5 (s,3), 2.41 (s,3), 1.75 (s,3) ppm;

3-[3,5-difluoro-4-methyl-6-[3-(2-methyl-1-oxopropyl)]phenoxy]pyridin-2-yl)oxy]benzamidine,acetic acid salt; NMR (CDCl₃) 10.2 (br,4), 7.7 (m,1), 7.2-7.6 (m,7),3.45 (m,1), 2.39 (s,3), 1.88 (s,3), 1.14 (m,6) ppm;

3-[(3,5-difluoro-4-methyl-6-(3-(dimethylaminocarbonyl)(hydroxy)methylphenoxy)pyridin-2-yl)oxy]benzamidine,acetic acid salt; NMR (DMSO-d₆) 10 (br,4), 7.55 (m,3), 7.4 (m,1), 7.3(t,1), 7.1 (m,3), 5.35 (s,1), 2.82 (s,6), 2.40 (s,3), 1.78 (s,3) ppm;

3-[3,5-difluoro-4-methyl-6-(3-(dimethylaminocarbonyl)(methoxy)methylphenoxy)pyridin-2-yl)oxy]benzamidine,acetic acid salt; NMR (DMSO-d₆) 10 (br,4), 7.5 (m,4), 7.4 (m,1), 7.3(m,2), 7.15 (d,1), 7.05 (m,2), 4.5 (s,1), 3.3 (s,3), 2.4 (s,3), 1.78(s,3) ppm; and

4-methoxy-3-[(3,5-difluoro-4-(ethoxycarbonylmethyl)(methyl)amino-6-(3-dimethylaminocarbonylphenoxy)pyridin-2-yl)oxy]benzamidine,acetic acid salt.

EXAMPLE 43-[(3,5-Difluoro-6-(3-dimethylaminophenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,Acetic Acid Salt

A.T3-[(3,5-difluoro-6-[3-dimethylaminophenoxy]-4-methylpyridin-2-yl)oxy]benzonitrile(1.4 g, 3.7 mmol) dissolved in ethanol (100 mL) and cooled to -10° C.was bubbled hydrochloric acid (g) until saturated. The mixture wasallowed to warm to ambient temperature and the solvent was removed invacuo. The residue was dissolved in ethanol (50 mL) and heated at refluxwhile ammonia (g) was bubbled through the reaction mixture for 2 hours.The solvent was removed in vacuo and the residue was partitioned with 2N aqueous potassium hydroxide and methylene chloride. The organic layerwas separated and dried (MgSO₄). Acetic acid (1 mL) was added and thesolvent was removed in vacuo. Crystallization from ether gave3-[(3,5-difluoro-6-(3-dimethyl-aminophenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; m.p. 176-179° C.

B. In a similar manner, the following compounds were made:

3-[(3,5-difluoro-6-(3-(2-(dimethylamino)ethyl)phenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; m.p. 214-216° C.;

3-[(3,5-difluoro-6-(3-aminocarbonylaminophenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,hydrochloride; NMR (DMSO-d₆) 9.4 (s,2), 9.25 (s,2), 9.1 (s,1), 7.6(m,2), 7.55 (m,2), 7.4 (s,1), 7.2 (t,1), 7.05 (d,1), 6.6 (d,1), 6.1(s,2), 2.4 (s,3), 2.1 (s,3), 1.8 (s,3) ppm;

3-[(3,5-difluoro-6-(3-ethoxycarbonylphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; m.p. 198-199° C.;

3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; m.p. 160-163° C.;

3-[(3,5-difluoro-6-[3-(ethylamino)phenoxy]-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; m.p. 193-196° C.;

3-[(6-(3-diethylarinophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; m.p. 196-197° C.;

3-[(3,5-difluoro-4-methyl-6-[3-(phenylamino)phenoxy]pyridin-2-yl)oxy]benzamidine,acetic acid salt; NMR (DMSO-d₆) 10.0 (br,4), 8.4 (s,1), 7.4-7.7 (m,4),7.3 (t,2), 7.2 (t,1), 7.1 (d,2), 6.9 (m,2), 6.8 (s,1), 6.5 (d,1), 2.4(s,3), 1.8 (s,3) ppm;

3-[(3,5-difluoro-6-(3-methylaminocarbonylphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; NMR (DMSO-d₆) 10.3 (br,4), 8.5 (s,1), 7.6 (d,1), 7.55(m,3), 7.4 (m,3), 2.8 (d,3), 2.4 (s,3), 1.75 (s,3) ppm;

3-[(3,5-difluoro-6-(3-(4-methylpiperazin-1-oyl)phenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; NMR (DMSO-d₆) 10.3 (br,4), 7.6 (m,3), 7.45 (m,2), 7.25(m,1), 7.1 (m,2), 3.6 (br,2), 3.2 (br,2), 2.4 (s,3), 2.35 (br,2), 2.2(br,2), 2.2 (s,3), 1.8 (s,3) ppm;

3-[(3,5-difluoro-6-(3-(piperidin-1-oyl)phenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; NMR (DMSO-d₆) 10.3 (br,4), 7.6 (m,3), 7.45 (m,2), 7.2(d,1), 7.15 (m,2), 3.6 (br,2), 3.2 (br,2), 2.4 (s,3), 1.8 (s,3) 1.3-1.6(m,6) ppm;

3-[(3,5-difluoro-6-(3-(methyl)(benzyl)aminocarbonylphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; m.p. 167-169° C.;

3-[(3,5-difluoro-6-(3-(methyl)(2-pyridin-1-ylethyl)aminocarbonylphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; m.p. 145-150° C.;

3-[(3,5-difluoro-6-(3-(methyl)(ethyl)aminocarbonylphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; NMR (DMSO-d₆) 10.2 (br,4), 8.5 (m,1), 7.1-7.7 (m,8),3.4 (br,1), 3.05 (br,1), 1.8 (m,3), 2.4 (s,3), 1.75 (s,3) 1.1 (m,1.5),1.0 (m,1.5) ppm;

3-[(3,5-difluoro-6-(3-diethylaminocarbonylphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; NMR (DMSO-d₆) 10.3 (br,4), 7.5 (m,3), 7.2 (m,2), 7.2(d,1), 7.1 (m,2), 3.4 (br,2), 3.05 (br,2), 2.4 (s,3), 1.8 (s,3) 1.15(br,3), 1.0 (br,3) ppm;

3-[3,5-difluoro-6-(3-(carboxyethyl)aminocarbonylphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,ethyl ester, acetic acid salt;

3-[(6-(3-chlorophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; m.p. 200-202° C.;

3-[(3,5-difluoro-4-methyl-6-(3-trifluoromethylphenoxy)pyridin-2-yl)oxy]benzamidine,acetic acid salt; m.p. 192-193° C.;

3-[3,5-difluoro-6-(3-methoxyphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; m.p. 182-185° C.;

3-[(3,5-difluoro-6-(3-fluorophenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; m.p: 208-209° C.;

3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-methylpyridin-2-yl)oxy]-4-methylbenzamidine, acetic acid salt; m.p. 192-193° C.;

3-[(3,5-difluoro-4-methyl-6-[3-[(phenyl)oxomethyl]phenoxy]pyridin-2-yl)oxy]benzamidine,acetic acid salt; m.p. 162-165° C.;

3-[3,5-difluoro-6-(3-hydroxyphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; m.p. 114-117° C.;

5-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-methylpyridin-2-yl)oxy]-2-methoxy-benzamidine,acetic acid salt; NMR (DMSO-d₆) 9.8 (br,4), 7.75 (d,1), 7.7 (s,1), 7.3(d,1), 7.05 (t,1), 6.45 (d,1), 6.3 (s,1), 6.15 (d,1), 3.8 (s,3), 2.85(s,6), 2.4 (s,3), 1.8 (s,3) ppm;

3-[(6-(3-ethoxycarbonylmethylphenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; NMR (DMSO-d₆) 10.0 (br,4), 7.55 (m,3), 7.45 (m,1),7.25 (m,1), 7.05 (m,3), 4.05 (q,2), 3.65 (s,2), 2.4 (s,3), 1.8 (s,3),1.2 (t,3) ppm;

3-[(6-(-ethoxycarbonylmethylphenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzamidine;

3-[(6-(3-(2-(ethoxycarbony)ethyl)phenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzenepropionicacid, ethyl ester, acetic acid salt; NMR (DMSO-d₆) 10.2 (br,4), 7.55(m,3), 7.45 (m,1), 7.25 (t,1), 7.0 (m,3), 4.05 (q,4), 2.8 (t,2), 2.6(m,2), 2.4 (s,3), 1.8 (s,3), 1.2 (t,3) ppm;

3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-methylpyridin-2-yl)oxy]-2,6-dimethoxybenzamidine,acetic acid salt; m.p. 109-111° C.;

3-[(3,5-difluoro-6-(3-(2-hydroxyethyl)phenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; m.p. 179-182° C.;4-methoxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; NMR (DMSO-d₆) 9.6 (br,4), 7.7 (d,1), 7.6 (s,1), 7.3(t,1), 7.2 (d,1), 7.05 (d,1), 7.0 (d,1), 6.9 (s,1), 3.8 (s,3), 3.1(s,6), 2.95 (s,3), 2.8 (s,3), 1.75 (s,3) ppm;

4-methoxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-ethoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine,acetic acid salt; NMR (DMSO-d₆) 10.0(br,4),7.65 (m,2), 7.3 (m,1), 7.2(m,1), 7.0 (m,3), 4.1 (q,2), 3.8 (s,3), 3.7 (m,2), 3.3 (m,2), 3.0 (s,3),2.8 (s,3), 2.7 (m,1), 2.0 (m,2), 1.75 (s,3), 1.25 (t,3) ppm; and

4-methoxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(3-ethoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine,acetic acid salt; NMR (DMSO-d₆) 9.2 (br,4), 7.8 (d,1), 7.7 (s,1), 7.3(m,2), 7.0 (m,3), 4.1 (q,2), 3.8 (s,3), 3.7 (m,1), 3.4 (m,5), 3.0 (s,3),2.8 (s,3), 2.7 (m,1), 2.0 (s,3), 1.8 (m,4), 1.1 (t,3) ppm.

EXAMPLE 54-Amino-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,Acetic Acid Salt

A. In a manner similar to Example 1 above,4-amino-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-methylpyridin-2-yl)oxy]benzenecarbonitrilewas reacted with hydrogen chloride and ammonia. The resulting residuewas purified by HPLC on a C18 Dynamax column with a 20-80% acetonitrilein water gradient with 0.1% trifluoroacetic acid and the material waspartitioned with ethyl acetate and aqueous sodium bicarbonate. Theorganic layer was separated, dried (MgSO₄), and the solvent was removedin vacuo. The residue was dissolved in water, acidified with aceticacid, and the solvent removed to give4-amino-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt; NMR (DMSO-d₆) 10 (br,4), 7.45 (m,2), 7.03 (t,1), 6.79(d,1), 6.44 (dd,1), 6.33 (t,1), 6.29 (d,1), 6.16(s,1), 3.36 (s,2), 2.84(s,6), 2.38 (s,3), 1.76 (s,3) ppm.

B. In a simiiiar manner, the following compound was made:

4-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-methylpyridin-2-yl)amino]-3-hydroxybenzamidine,acetic acid salt; NMR (DMSO-d₆) 10.94 (s,1), 9.01 (s,2), 8.71 (s,2),7.86 (d,1), 7.65 (s,1), 7.26 (t,1), 7.19 (d,1), 6.89 (dd,1), 6.64(dd,1), 6.54 (m,1), 6.44 (dd,1), 3.4 (s,1), 2.90 (s,6), 2.32 (s,3) ppm.

EXAMPLE 64-Hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,Trifluoroacetic Acid Salt

A. To5-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-methylpyridin-2-yl)oxy]-4-methoxybenzamidine,trifluoroacetic acid salt (0.80 g, 1.9 mmol) in methylene chloride (70mL) at -78° C. was added boron tribromide (1 M in methylene chloride, 9mL, 9 mmol). The reaction was warmed to ambient temperature. Afterstirring for 16 hours, the reaction was concentrated and purified byHPLC as described above in Example 5 to give4-hydroxy-3-[3,5-difluoro-6-(3-dimethylaminophenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.06 (s,2), 8.88 (s,2), 7.67(m,1), 7.62 (d,1), 7.1 (d,1), 7.04 (t,1), 6.45 (d,1), 6.32 (m,1), 6.23(d,1), 2.85 (s,6), 2.4 (s,3) ppm.

B. In a similar manner, the following compounds were made:

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-dimethylaminopyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 11.0 (s,1), 9.0 (s,2), 8.8(s,2), 7.6 (m,2), 7.3 (t,1), 7.0 (m,4), 3.1 (s,6), 2.95 (s,3), 2.8 (s,3)ppm;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-ethoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine,acetic acid salt; NMR (DMSO-d₆) 11.0 (s,1), 9.0 (s,2), 8.9 (s,2), 7.55(m,2), 7.3 (t,1), 7.0 (m,4), 4.1 (q,2), 3.6 (m,2), 3.3 (m,2), 3.0 (s,3),2.8 (s,3), 2.6 (m,1), 2.0 (m,2), 1.7(s,2), 1.15 (t,3) ppm;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(3-ethoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine,acetic acid salt; NMR (DMSO-d₆) 9.2 (br,4), 7.6 (m,2), 7.3 (t,1), 7.0(m,4), 4.1 (q,2), 3.8 (s,3), 3.2-3.7 (m,4), 3.0 (s,3), 2.8 (s,3), 2.7(m,1), 2.0 (s,3), 1.8 (m,4), 1.1 (t,3) ppm;

4-hydroxy-3-[(6-(3-dimethylaminocarbonylphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 11.0 (s,1), 9.1 (s,2), 8.85(s,2), 7.9 (t,1), 7.6 (m,2), 7.4 (t,1), 7.15 (m,2), 7.05 (m,2), 6.75(d,1), 6.7 (d,1), 2.95(s,3) 2.8 (s,3) ppm;

4-hydroxy-3-[(6-(3-dimethylaminocarbonylphenoxy)-4-(4-methylpiperazin-1-oyl)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 11.0 (s,1), 10.1 (br,1), 9.05(s,2), 8.85 (s,2), 7.6 (m,2), 7.4 (t,1), 7.2 (m,2), 7.05 (m,2), 6.8(s,1), 6.7 (s,1), 3.5 (m,8), 2.95 (s,3), 2.8 (s,3) ppm;

4-hydroxy-3-[(3,5-difluoro-6-(5-hydroxy-3-dimethylaminocarbonylphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 11.0 (s,1), 9.9 (s,1), 9.0(s,2), 8.8 (s,2), 7.6 (m,2), 7.0 (d,1), 6.5 (s,1), 6.4 (s,1), 6.3 (s,1),2.9 (s,3), 2.7 (s,3), 2.4 (s,3) ppm;

4-hydroxy-3-[3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (CDCl₃) 11.20 (bs,1), 8.98 (s,2), 8.66(s,2), 7.59 (s,1), 7.53 (d,1), 7.29 (t,1), 7.18-6.92 (m,4), 2.96 (s,3),2.78 (s,3), 2.36 (s,3), 1.91 (s,1.5) ppm;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 11.1 (s,1), 9.0 (s,2), 8.8(s,2), 7.6 (m,2), 7.3 (t,1), 7.0-7.1 (m,4), 5.2 (q,2), 3.0 (s,3), 2.8(s,3), ppm;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-hydroxypyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (CD₃ CN) 8.7 (s,2), 7.5 (s,2), 7.3-7.4(m,4), 7.2 (dt,1), 7.1 (dd,1), 7.0 (t,1), 6.8 (d,1), 3.1 (s,3), 3.0(s,3) ppm;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1,3-difluoroprop-2-oxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (CD₃ CN) 9.8 (s,2), 7.3-7.4 (m,4), 7.2(d,1), 7.1 (d,1), 7.0 (s,1), 6.8 (d,1), 5.1 (t,1), 4.8 (d,4), 3.1 (s,3),3.0 (s,3) ppm;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-bromo-3-fluoroprop-2-oxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (CD₃ CN) 10.8 (s,2), 7.3-7.4 (m,4), 7.2(d,1), 7.1 (d,1), 7.0 (s,1), 6.8 (d,1), 5.1 (m,1), 4.9(d,1), 4.7 (d,1),3.8 (d,1), 3.1 (s,3), 3.0 (s,3) ppm;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1,3-dibromoprop-2-oxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 11.1 (s,1), 9.0 (s,2), 8.8(s,2), 7.5-7.6 (m,2), 7.3 (t,1), 7.1 (m,2), 7.0 (m,2), 5.1 (t,1), 3.9(d,4), 3.0 (s,3), 2.8 (s,3) ppm;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-((methyl)(carboxymethyl)mino)pyridin-2-yl)oxy]benzamidine,hydrochloride salt; NMR (DMSO-d₆) 9.0 (s,2), 8.7 (s,2), 7.6 (m,2), 7.2(t,1), 7.0 (m,4), 4.1 (s,2), 3.2 (s,3), 2.9 (s,3), 2.8 (s,3) ppm;

4-hydroxy-3-[(6-(3-dimethylaminocarbonylphenoxy)-4-carboxypyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 11.12 (s,2), 9.16 (s,2), 9.03(s,2), 7.3 (m,9), 2.99 (s,3), 2.87 (s,3) ppm;

4-hydroxy-3-[6-(3-dimethylaminocarbonylphenoxy)-4-(aminocarbonyl)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 11.0 (s,1), 9.06 (s,2), 8.76(s,2), 8.3 (s,1), 7.85 (s,1), 7.3 (m,9), 2.98 (s,3), 2.86 (s,3) ppm;

4-hydroxy-3-[(6-(3-dimethylaminocarbonylphenoxy)-4-(dimethylaminocarbonyl)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 10.95 (s,1), 9.08 (s,2), 8.72(s,2), 7.3 (m,7), 6.72 (s,1), 6.66 (s,1), 2.95 (m,12) ppm;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-ethoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(3-ethoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phonoxy)-4-(2-hydroxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; and

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-hydroxy-4-methoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt.

C. In a similar manner, the following compounds are made:

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-hydroxy-4-methoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-hydroxy-4-methoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;and

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-hydroxy-4-methoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine.

EXAMPLE 74-Hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(piperidin-1-yl)pyridin-2-yl)oxy]benzamidine,Trifluoroacetic Acid Salt

A. In a manner similar to Example 1,3-[(6-(5-cyano-2-(benzyloxy)phenoxy)-3,5-difluoro-4-(piperidin-1-yl)pyridin-2-yl)oxy]-N,N-dimethylbenzamidewas reacted with HCl and ammonia. The solvent was removed in vacuo. Thematerial was dissolved in methanol and Pd(C) was added. The reaction wasplaced under an atmosphere of hydrogen at 50 psi for 2 hours. Thereaction was filtered through celite and the solvent was removed invacuo. The material was partially dissolved in 0.25 N aqueous potassiumhydroxide and the solid was removed by filtration. The solid waspurified by HPLC as described above in Example 5 to give4-hydroxy-3-[(3,5-difluoro-6-(3-dimethyl-aminocarbonylphenoxy)-4-(piperidin-1yl)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt, as the final product; NMR (DMSO-d₆) 11.0(s,1), 9.0 (s,2), 8.7 (s,2), 7.6 (m,2), 7.3 (t,1), 7.0 (m,4), 3.4 (m,4),2.95 (s,3), 2.8 (s,3), 1.65 (m,6) ppm.

B. In a similar manner, the following compounds were made:

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-methylpiperazin-1-yl)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 11.2 (s,1), 10.3 (br,1), 9.0(s,4), 7.6 (m,2), 7.3 (m,2), 7.0 (m,4), 3.6 (m,8), 3.0 (s,3), 2.9 (s,3),2.8 (s,3), 1.65 (m,6) ppm;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-(ethoxycarbonylmethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine,acetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-amidinophenoxy)-4-(ethoxycarbonyl)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (CDCl₃) 11.14 (s,1), 9.37-8.88 (m,8),7.76-7.06 (m,9), 4.35 (q,2), 1.32 (t,3) ppm;

4-hydroxy-3-[3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(morpholin-4-yl)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.0 (s,2), 8.6 (s,2), 7.5(m,2), 7.3 (t,1), 7.0 (m,4), 3.7 (m,4), 3.4 (m,4), 2.9 (s,3), 2.8 (s,3)ppm;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(methyl)(phenyl)aminocarbonylpyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-methoxypyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-carbonylphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxy-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-methoxy-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(4-ethoxycarbonylphenoxy]pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-(prop-2-oxycarbonyl)methylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-(ethoxycarbonyl)ethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-(ethoxycarbonyl)methylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2,6-dimethoxy-4-methoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2,6-dimethoxy-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-guanidinophenoxy)-4-(1-(ethoxycarbonyl)methylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-(1-(ethoxycarbonyl)ethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-(ethoxycarbonylmethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(5-ethoxycarbonylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 11.35 (s,1), 10.41 (s,1), 9.03(d,4), 7.35-7.62 (m,6), 7.0 (d,1), 5.57 (s,1), 4.64 (dd,1), 4.22 (q,2),4.05 (dd,2), 3.95 (dd,1), 3.78 (d,1), 3.65 (d,1), 2.96 (s,3), 2.75(m,1), 2.55 (m,1), 1.23 (t,3) ppm;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(5-ethoxycarbonylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(1-methoxycarbonylmethylpiperidin-4-yloxy)pyridin-2-yl)oxylhen/amidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-ethoxycarbonylmethylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(1-aminocarbonylmethylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-2-(3,5-di(ethoxycarbonyl)phenoxy)pyridin-4-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-dichloro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-benzylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-ethoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazotin-2-yl)phenoxy)-4-(3-ethoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(dimethylaminomethyl)phenoxy)-4-(2-methoxy-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,3-dimethoxy-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-aminocarbonyl-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-(1-methylimidazolin-2-yl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethoxy-4-methoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethoxy-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2,6-dimethoxy-4-aminocarbonylphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-amidinophenoxy)-4-(2-methoxy-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy)benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(6-(3-amidinophenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-chloro-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethyl-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-(2-ethoxycarbonylethylphenoxy)pyridin-2-yl)oxy]benzamidine, trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-ethoxycarbonylmethylphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-5-(tetrazol-5-yl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxyphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-methoxypyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-propoxypyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-ethoxycarbonylmethylpiperazinyl)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((methyl)(ethoxycarbonylmethyl)amino)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydoxy-3-[(3,5-dichloro-6-(3-dimethylaminocarbonylphenoxy)-4-(tetrahydrofuran-3-oxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-dichloro-6-(3-dimethylaminocarbonylphenoxy)-4-(piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-dichloro-6-(3-dimethylaminocarbonylphenoxy)-4-(piperidin-3-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(aminocarbonylmethoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-dichloro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-(carboxymethyl)pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-2-methoxypyridin-4-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-2-(2-methoxy-5-ethoxycarbonylphenoxy)pyridin-4-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[3-(3-dinethylaminocarbonylphenoxy)-4-(methylamino)carbonylaminophen-1-yloxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3-(3-dimethylaminocarbonylphenoxy)-2,4,6-trichloro-5-fluorophen-1-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((piperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-benzylpiperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((piperidin-4-yl(methyl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-benzylpiperidin-4-yl)(methyl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-(1-(methoxycarbonyl)ethyl)piperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-aminocarbonylphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-(1-(hydroxymethyl)ethoxycarbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-(prop-2-oxycarbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-(2-(methoxy)ethoxycarbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-n-butoxycarbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-((2-(2-hydroxyethoxy)ethoxy)carbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-((2-(2-methoxyethoxy)ethoxy)carbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-(2-(aminocarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-(2-(methoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-(2-(methoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2yl)plienoxy)-4-(2-methoxy-4-(2)-chloro-1-methylethoxycarbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-1-methylimidazolin-2-yl)phenoxy)-4-(3-(2-(ethoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-(2-(ethoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethoxy-4-(2-ethoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; and

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt.

C. In a similar manner, the following compounds are made:

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-(1-methyl-1-(ethoxycarbonyl)ethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-(1-methyl-1-(ethoxycarbonyl)ethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(4-(1-methyl-1-(ethoxycarbonyl)ethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(4-(1-methyl-1-(ethoxycarbonyl)ethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2,3-dimethoxy-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(5-aminocarbonylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(5-aminocarbonylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(5-aminocarbonylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(5-aminocarbonylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-methylcarbonylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-methylcarbonylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(1-methylcarbonylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(1-methylcarbonylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((ethoxycarbonyl)methoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimetflylaminocarbonylphenoxy)-4-((ethoxycarbonyl)methoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-((ethoxycarbonyl)methoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-((ethoxycarbonyl)methoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-ethyl-5-ethoxycarbonylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-ethyl-5-ethoxycarbonylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(1-ethyl-5-ethoxycarbonylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(1-ethyl-5-ethoxycarbonylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-(tetrazol-5-ylmethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-(tetrazol-5-ylmethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(1-(tetrazol-5-ylmethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(1-(tetrazol-5-ylmethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-(tetrazol-5-yl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxy-5-(tetrazol-5-yl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-4-(tetrazol-5-yl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-methoxy-4-(tetrazol-5-yl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-chloro-4-(tetrazol-5-yl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-chloro-4-(tetrazol-5-yl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-chloro-4-(tetrazol-5-yl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-chloro-4-(tetrazol-5-yl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-chlorophenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylarinocarbonylphenoxy)-4-(2-chlorophenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-chlorophenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-chlorophenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-ethoxycarbonyl-1-methylethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-ethoxycarbonyl-1-methylethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(1-ethoxycarbonyl-1-methylethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(1-ethoxycarbonyl-1-methylethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((2-ethoxycarbonylethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-((2-ethoxycarbonylethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-((2-ethoxycarbonylethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-((2-ethoxycarbonylethy)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-methoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(morpholin-4-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(morpholin-4-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxV-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(morpholin-4-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(piperidin-1-yl)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(piperidin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(piperidin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-methoxypyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)-4-methoxypyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-methoxypyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-(prop-2-oxycarbonyl)methylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(1-(prop-2-oxyycarbonyl)methylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(1-(prop-2-oxycarbonyl)methylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-(ethoxycarbony)ethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(1-(ethoxycarbonyl)ethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(1-(ethoxycarbonyl)ethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-ethoxycarbonylmethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(1-ethoxycarbonylmethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-(1-(ethoxycarbonyl)ethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(4-(1-(ethoxycarbonyl)ethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(4-(1-(ethoxycarbonyl)ethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(4-ethoxycarbonylmethylpiperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-((3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(4-ethoxycarbonylmethylpiperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(5-ethoxycarbonylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(5-ethoxycarbonylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)-4-(pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-ethoxycarboxylmethylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)-4-(1-ethoxycarbonylmethylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(1-ethoxycarbonylmethylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-dichloro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-benzylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-dichloro-6-(3-(guanidino)phenoxy)-4-(1-benzylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[3,5-dichloro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(1-benzylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxy-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-methoxy-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(4-ethoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(4-ethoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(3-ethoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(3-ethoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2,3-dimethoxy-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2,3-dimethoxy-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(3-aminocarbonyl-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(3-aminocarbonyl-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(3-aminocarbonyl-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(3-(1-methylimidazolin-2-yl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(3-(1-methylimidazolin-2-yl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(3-(1-methylimidazolin-2-yl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(3-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(3-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(3-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2,6-dimethoxy-4-methoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2,6-dimethoxy-4-methoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2,6-dimethoxy-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2,6-dimethoxy-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethoxy-4-aminocarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2,6-dimethoxy-4-aminocarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2,6-dimethoxy-4-aminocarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-chloro-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difiuoro-6-(3-(guanidino)phenoxy)-4-(2-chloro-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-chloro-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2,6-dimethyl-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2,6-dimethyl-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2,6-dimethyl-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(3-(2-ethoxycarbonylethyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(3-(2-ethoxycarbonylethyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(3-(2-ethoxycarbonylethyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxy-4-ethoxycarbonylmethylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-4-ethoxycarbonylmethylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-methoxy-4-ethoxycarbonylmethylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxy-5-(tetrazol-5-yl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-5-(tetrazol-5-yl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-methoxy-5-(tetrazol-5-yl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-methoxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-propoxypyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-propoxypyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-propoxypyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-((methyl)(ethoxycarbonylmethyl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)-4-((methyl)(ethoxycarbonylmethyl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-((methyl)(ethoxycarbonylmethyl)amino)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(aminocarbonylmethoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(aminocarbonylmethoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(aminocarbonylmethoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-((piperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-((piperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-((piperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-((1-benzylpiperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-((1-benzylpiperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-((1-benzylpiperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-((piperidin-4-yl)(methyl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-((piperidin-4-yl)(methyl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-((piperidin-4-(methyl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-((1-benzylpiperidin-4-yl)(methyl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-((1-benzylpiperidin-4-yl)(methyl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-((1-benzylpiperidin-4-yl)(methyl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-((1-(1-(methoxycarbonyl)ethyl)piperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-((1-(1-(methoxycarbonyl)ethylpiperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-((1-(1-(methoxycarbonyl)ethylpiperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxy-4-aminocarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-4-aminocarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-methoxy-4-aminocarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxy-4-(1-(hydroxymethyl)ethoxycarbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-4-(1-(hydroxymethyl)ethoxycarbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-methoxy-4-(1-(hydroxymethyl)ethoxycarbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxy-4-(prop-2-oxyCarbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-4-(prop-2-oxycarbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-methoxy-4-(prop-2-oxycarbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxy-4-(2-(methoxy)ethoxyCarbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-4-(2-(methoxy)ethoxyCarbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-methoxy-4-(2-(methoxy)ethoxycarbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxy-4-n-butoxycarbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-4-n-butoxycarbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-methoxy-4-n-butoxycarbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxy-4-((2-(2-hydroxyethoxy)ethoxy)carbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-4-((2-(2-hydroxyethoxy)ethoxy)carbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-methoxy-4-((2-(2-hydroxyethoxy)ethoxy)carbonyl)phenoxy)pyridin-2-yl)oxy] benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxy-4-((2-(2-methoxyethoxy)ethoxy)carbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-4-((2-(2-methoxyethoxy)ethoxy)carbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine9;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-methoxy-4-((2-(2-methoxyethoxy)ethoxy)carbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(3-(2-(aminocarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(3-(2-(aminocarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(3-(2-(aminocarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(3-(2-(methoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(3-(2-(methoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(3-(2-(methoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-(2-(methoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(4-(2-(methoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(4-(2-(methoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxy-4-(2-chloro-1-methylethoxycarbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-4-(2-chloro-1-methylethoxycarbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-methoxy-4-(2-chloro-1-methylethoxycarbonyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(3-(2-(ethoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(3-(2-(ethoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(3-(2-(ethoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-(2-(ethoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(4-(2-(ethoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(4-(2-(ethoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2,6-dimethoxy-4-(2-(ethoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2,6-dimethoxy-4-(2-(ethoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2,6-dimethoxy-4-(2-(ethoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-methylpiperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(4-methylpiperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(4-methylpiperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-dimethylaminopyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-dimethylaminopyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-dimethylaminopyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-methylpyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-methylpyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-methylpyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1,3-difluoroprop-2-oxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(1,3-difluoroprop-2-oxy)pyridin-2-yl)oxy]benzamidine;and

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(1,3-difluoroprop-2-oxy)pyridin-2-yl)oxy]benzamidine.

EXAMPLE 84-Hydroxy-3-[(3,5-difluoro-6-(3-(imidazol-1-yl)phenoxy)-4-(carboxy)pyridin-2-yl)oxy]benzamidine,Trifluoroacetic Acid Salt

A. In a manner similar to Example 6,2-(5-amidino-2-hydroxyphenoxy)-6-(3-(imidazol-1-yl)phenoxy)pyridine-4-carboxylicacid, ethyl ester was reacted with boron tribromide. The resulting oilwas dissolved in 6 N HCl and heated at reflux for 2 hours. Concentrationof the mixture in vacuo and purification by HPLC as described above inExample 5 gave4-hydroxy-3-[(3,5-difluoro-6-(3-(imidazol-1-yl)phenoxy)-4-(carboxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d6, TFA) 9.7 (s,1), 9.0 (s,2), 8.8(s,2), 8.3 (s,1), 7.9 (s,1), 7.6 (m,5), 7.3 (m,1), 7.1 (m,2), 7.0 (m,1)ppm.

B. In a similar manner, the following compound was made:

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(carboxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 11.0 (s,1), 9.1 (s,2), 8.7(s,2), 7.7 (m,2), 7.2 (m,2), 7.0 (s,1), 6.8 (s,1), 6.6 (d,1), 6.4 (m,2),2.8 (s,6) ppm.

EXAMPLE 93,3'-[4-Aminocarbonyl-2,6-pyridinediylbis(oxy)]bis(benzamidine),Trifluoroacetic Acid Salt

A. In a manner similar to Example 1 above, reaction of3,3'-[4-ethoxy-carbonyl-2,6-pyridinediylbis(oxy)]bis(benzonitrile) gave3,3'-[4-aminocarbonyl-2,6-pyridinediylbis(oxy)]bis(benzamidine), whichwas purified by HPLC as described above in Example 5 to give thetrifluoroacetic acid salt, m.p. >210° C.; NMR (DMSO-d₆) 9.3 (s,4), 9.1(s,4), 8.3 (s,1), 7.8 (s,1), 7.65 (m,4), 7.55 (m,4), 7.2 (s,2) ppm.

B. In a similar manner, the following compounds were made:

3,3'-[3-aminocarbonyl-2,6-pyridinediylbis(oxy)]bis(benzamidine),trifluoroacetic acid salt; NMR (DMSO) 9.45 (br s,4), 9.35 (br s,4), 8.4(d,1), 7.4-7.9 (m,10), 6.95 (d,1) ppm; and

4-methoxy-3-[(6-(3-dimethylaminophenoxy)-4-aminocarbonylpyridin-2-yl)oxy]benzamidinehydrochloride, NMR (DMSO-d₆) 9.3 (s,2), 9.1 (s,2), 8.3 (s,1), 7.8 (m,2),7.3 (s,1), 7.1 (m,3), 6.9 (s,1), 6.5 (d,1), 6.3 (m,2), 3.8 (s,3), 2.8(s,6) ppm.

EXAMPLE 10 2,6-bis(3-Amidinophenoxy)pyridine-3-carboxylic acid,Dihydrochloride

A. In a manner similar to Example 2 above,2,6-bis(3-amidinophenoxy)pyridine-3-carboxylic acid, ethyl ester (0.20g, 0.31 mmol) was dissolved in 5 M HCl and heated for 2 hours at 80° C.The solvent was removed in vacuo to give2,6-bis(3-amidinophenoxy)pyridine-3-carboxylic acid, dihydrochloride;NMR (DMSO-d₆) 9.5 (br s,4), 9.35 (br s,4), 8.45 (d,1), 7.7 (m,2), 7.6(m,2), 7.5 (m,4), 6.95 (d,1) ppm.

B. In a similar manner, the following compounds were made and purifiedby HPLC as described above in Example 5:

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(ethoxycarbonylmethoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(3,5-dicarboxyphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-methoxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-5-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,3-dimethoxy-5-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethoxy-4-(2-carboxyethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethoxy-4-(2-carboxyethyl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-(2-carboxyethyl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-(2-carboxyethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-(2-carboxyethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(dimethylaminomethyl)phenoxy)-4-(2-methoxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3,5-dicarboxyphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-carboxy-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethoxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2,6-dimethoxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-carboxymethylphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-amidinophenoxy)-4-(2-methoxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-chloro-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethyl-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-((2-dimethylaminoethyl)(carboxymethyl)amino)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-((2-dimethyl-

aminoethyl)(carboxymethyl)amino)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-carboxymethylpiperidin-4-yl)(methyl)amino)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 11.25 (s,1), 10.30 (s,1), 9.03(br s,4), 7.58-7.55 (m,2), 7.50 (t,1), 7.38-7.31 (m,3), 7.03 (d,1), 4.10(s,2), 4.08-3.88 (m,4), 3.66 (m,2), 3.16 (m,2), 2.95 (s,6), 2.26 (m,2),1.93(m,2) ppm;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-carboxymethylpiperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((methyl)(carboxymethyl)amino)pyridin-2-yl)oxy]benzamidine,hydrochloride salt; NMR (DMSO-d₆) 11.25 (s,1), 10.45 (s,1), 9.1 (d,4),7.35 (m,7), 4.18 (s,2), 4.05 (m,4), 3.2 (s,3), 2.95 (s,3) ppm;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt.

C. In a similar manner, the following compounds are made:

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-(1-methyl-1-(carboxy)ethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-(1-methyl-1-(carboxy)ethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(4-(1-methyl-1-(carboxy)ethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(4-(1-methyl-1-(carboxy)ethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-(1-(carboxy)ethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-(1-(carboxy)ethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(4-(1-(carboxy)ethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(4-(1-(carboxy)ethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((2-carboxyethyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-((2-carboxyethyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-((2-carboxyethyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-((2-carboxyethyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-(1-(carboxy)ethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-(1-(carboxy)ethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(1-(1-(carboxy)ethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(1-(1-(carboxy)ethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-(1-carboxy-1-methylethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-(1-carboxy-1-methylethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(1-(1-carboxy-1-methylethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(1-(1-carboxy-1-methylethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidihe;

4-hydroxy-3-[(6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-carboxymethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(6-(3-dimethylaminocarbonylphenoxy)-4-(1-carboxymethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(6-(3-(guanidino)phenoxy)-4-(1-carboxymethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(1-carboxymethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(carboxymethoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(carboxymethoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(carboxymethoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(carboxymethoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-5-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-methoxy-5-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2,3-dimethoxy-5-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2,3-dimethoxy-5-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(3-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(3-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(3,5-dicarboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(3,5-dicarboxyphenoxy)pyridin-2-yloxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(3-carboxy-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(3-carboxy-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(3-carboxy-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2,6-dimethoxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-chloro-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-chloro-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2,6-dimethyl-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2,6-dimethyl-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-((1-carboxymethylpiperidin-4-yl)(methyl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-((1-carboxymethylpiperidin-4-yl)(methyl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-((1-carboxymethylpiperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-((1-carboxymethylpiperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-4-carboxymethylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-methoxy-4-carboxymethylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-((methyl)(carboxymethyl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-((methyl)(carboxymethyl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2,6-dimethoxy-4-(2-carboxyethenyl)prieiioxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2,6-dimethoxy-4-(2-carboxyethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(3-(2-carboxyethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(3-(2-carboxyethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(4-(2-carboxyethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(4-(2-carboxyethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2,6-dimethoxy-4-(2-carboxyethyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2,6-dimethoxy-4-(2-carboxyethyl)phenoxy)pyridin-2-ylsoxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(3-(2-carboxyethyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(3-(2-carboxyethyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-(carboxymethyl)pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(1-(carboxymethyl)pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(1-(carboxymethyl)pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((2-dimethylaminoethyl)(carboxymethyl)amino)pyridin-2-yl)oxy]benzamidine;and

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-((2-dimethylaminoethyl)(carboxymethyl)amino)pyridin-2-yl)oxy]benzamidine.

EXAMPLE 114-Hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(1-(ethoxycarbonylmethyl)pyrrolidin-3-yloxy)pyridin-2-yloxy]benzamidine,Trifluoroacetic Acid Salt

A. To ethanol (40 mL) was added4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(pyrrolidin-3-yloxy)pyridin-2-yloxy]benzamidine(0.44 g, 0.90 mmol), ethyl bromoacetate (0.15 g, 0.9 mmol), andtriethylamine (0.11 g, 1.1 mmol). After stirring for 19 hours, thereaction mixture was concentrated and purified by HPLC as describedabove in Example 5 to give4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylamino-phenoxy)-4-(1-(ethoxycarbonylmethyl)-pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt.

B. In a similar manner, the following compounds were made:

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-ethoxycarbonylmethylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-ethoxy-carbonylmethylpiperidin-4-yl)(methyl)amino)pyridin-2-yl)oxy]benzamidine,trifluoroacetic-acid salt; and

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-(ethoxycarbonylmethyl)piperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt.

C. In a similar manner, the following compounds are made:

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-((1-(ethoxycarbonylmethyl)piperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-((1-(ethoxycarbonylmethyl)piperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-((1-(ethoxycarbonylmethyl)piperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-((1-ethoxycarbonylmethylpiperidin-4-yl)(methyl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-((1-ethoxycarbonylmethylpiperidin-4-yl)(methyl)amino)pyridin-2-yl)oxy]benzamidine;and

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-((1-ethoxycarbonylmethylpiperidin-4-yl)(methyl)amino)pyridin-2-yl)oxy]benzamidine.

EXAMPLE 123-[(3,5-Difluoro-6-(3-carboxyphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,Hydrochloride Salt

A. To3-[(3,5-difluoro-6-(3-ethoxycarbonylphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,acetic acid salt (1.0 g, 2.0 mmol) dissolved in methanol (40 mL) wasadded 5N potassium hydroxide (20 mL). After stirring for 4 hours, thesolvent was removed in vacuo. The residue was dissolved in water (50 mL)and acidified with 12 N HCl. The resulting solid was filtered and washedwith ether to give3-[3,5-difluoro-6-(3-carboxyphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,hydrochloride salt; NMR (DMSO-d₆).9.3 (s,2), 9.1 (s,2), 7.7 (d,1), 7.65(s,1), 7.3-7.6 (m,6), 2.4 (s,3) ppm. If necessary the material can befurther purified by HPLC as described above in Example 5.

B. In a similar manner, the following compounds were made:

3-[(3,5-difluoro-6-(3-(2-carboxyethyl)aminocarbonylphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,m.p. 145-150° C.;

3-[(3,5-difluoro-6-(3-(2-carboxyethyl)phenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.3 (s,2), 9.2 (s,2), 7.6(m,4), 7.25 (t,1), 7.0 (m,2), 6.95 (m,1), 2.8 (t,2), 2.6 (m,2), 2.4(s,3) ppm;

3-[3,5-difluoro-6-(3-(carboxymethyl)phenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.3 (s,2), 9.2 (s,2), 7.6(m,4), 7.25 (t,1), 7.0 (m,3), 3,.4 (s,2), 2.4 (s,3) ppm;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-carboxypiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;NMR (DMSO-d₆) 9.75 (br,2), 8.5 (br,2), 7.5 (m,2), 7.3 (t,1), 7.0 (m,3),6.65 (d,1), 3.6 (m,2), 3.2 (m,2), 2.95 (s,3), 2.8 (s,3), 2.3 (m,1), 1.9(m,2), 1.7 (m,2) ppm;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(3-carboxypiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;NMR (DMSO-d₆) 9.75 (br,2), 8.7 (br,2), 7.5 (m,2), 7.3 (t,1), 7.0 (m,3),6.8 (d,1), 3.2-3.68 (m,4), 2.95 (s,3), 2.8 (s,3), 2.4 (m,1), 2.0 (m,1),1.8 (m,1), 1.6 (m,2) ppm;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-carboxymethylpiperazin-1-yl)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 11.1 (s,1), 9.0 (br,2), 8.9(br,2), 7.65 (m,2), 7.3 (m,1), 7.0 (m,4), 4.1 (s,2), 3.6 (m,8), 3.0(s,3), 2.8 (s,3), ppm;

4-hydroxy-3-[(6-(3-amidinophenoxy)-4-(carboxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (CDCl₃) 11.16 (s,1), 9.38-8.95 (m,8),7.68-7.04 (m,9) ppm;

3-[3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(N-methyl-N-carboxymethylamino)pyridin-2-yl)oxy]benzamidine;NMR (DMSO-d₆) 9.3 (s,2), 9.2 (s,2), 7.5 (m,4), 7.2 (t,1), 6.7 (m,2), 6.5(d,1), 4.2 (s,2), 3.2 (s,3), 2.9 (s,6) ppm;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-((methyl)(carboxymethyl)amino)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-carboxypiperidin-1-yl)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(5-carboxypyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 11.30 (s,1), 10.37 (s,1), 9.00(s,2), 8.99 (s,2), 7.61 (d,1), 7.57 (dd,1), 7.52-7.32 (m,4), 7.04 (d,1),6.55 (s,1), 4.52 (dd,1), 4.02 (dd,2), 3.88 (dd,2), 3.72 (dd,1), 3.58(d,1), 2.92 (s,3), 2.63 (dd,1), 2.44 (dd,1);

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-carboxymethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 11.29 (s,1), 10.31 (s,1), 9.05(s,2), 9.02 (s,2), 7.63-7.57 (m,2), 7.52 (t,1), 7.42-7.37 (m,3), 7.04(d,1), 4.92 (br s,1), 4.15 (s,2), 4.09-3.92 (m,4), 3.60-3.40 (m,4), 2.95(s,3), 2.32-2.10 (m,4) ppm;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-(1-carboxy-1-methylethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;NMR (DMSO-d₆) 11.34 (s,1), 10.46 (s,1), 9.21 (s,2), 8.99(s,2), 7.70(s,1), 7.63 (d,1), 7.54 (t,1), 7.43-7.40 (m,2), 7.15 (d,1), 4.96 (brs,1), 4.12-4.09 (m,2), 3.96-3.90 (m,2), 3.40-3.20 (m,4), 2.97 (s,3),2.40-2.30 (m,2), 2.28-2.14 (m,2), 1.54 (s,6) ppm;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(1-carboxymethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(carboxymethyl)(methyl)aminocarbonylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(1-carboxymethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-carboxypiperidin-1-yl)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(5-carboxypent-1-oxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-((methyl)(carboxymethyl)aminocarbonylmethyl)amino)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-carboxymethylpiperazin-1-yl)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-carboxymethoxypyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(1-(carboxymethyl)pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidinetrifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-(carboxymethyl)pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(6-(3-(2,4-dimethylimidazol-1-yl)phenoxy)-4-(carboxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(6-(3-(2-methylimidazol-1-yl)phenoxy)-4-(carboxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(6-(3-(4-methylimidazol-1-yl)phenoxy)-4-(carboxy)pyridin-2-yl)oxy]benzamidin,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(4-carboxymethylpiperazin-1-yl)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(4-carboxy-2-methoxyphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(4-carboxy-2-(morpholin-4-ylmethyl)phenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(carboxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(carboxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-amino-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-((methyl)(carboxymethyl)amino)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

3-hydroxy-4-[(6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(carboxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

3-hydroxy-4-[(6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(carboxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(6-(3-dimethylaminocarbonylphenoxy)-4-(carboxymethyl)(methyl)aminocarbonylpyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(4-carboxymethylpiperazin-1-yl)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(6-(3-dimethylaminophenoxy)-4-(4-carboxymethylpiperazin-1-oyl)pyridin-2-yl)oxy]benzamidine;and

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-aminocarbonyl-5-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt.

C. In a similar manner, the following compounds are made:

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxy-5-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2,3-dimethoxy-5-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(3-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(3,5-dicarboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2,6-dimethoxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-chloro-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2,6-dimethyl-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-((1-carboxymethylpiperidin-4-yl)(methyl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-((1-carboxymethylpiperidin-4-yl)amino)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxy-4-carboxymethylphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2,6-dimethoxy-4-(2-carboxyethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(3-(2-carboxyethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-(2-carboxyethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2,6-dimethoxy-4-(2-carboxyethyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(3-(2-carboxyethyl)phenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-carboxymethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(1-carboxymethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-hydroxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-hydroxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-hydroxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(3-carboxypiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(3-carboxypiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(4-carboxypiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(4-carboxypiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(5-carboxypent-1-oxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(5-carboxypent-1-oxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(5-carboxypent-1-oxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(4-carboxymethylpiperazin-1-yl)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylplenoxy)-4-(3-aminocarbonyl-5-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(3-aminocarbonyl-5-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(3-aminocarbonyl-5-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(5-carboxypyrrolidin-3-yloxypyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(5-carboxypyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(5-carboxypyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;

EXAMPLE 133-[(3,5-Difluoro-6-(3-((phenyl)hydroxymethyl)phenoxy)-4-methylpyridin-2-yl)oxy]benzamidine,Trifluoroacetic Acid Salt

A. To3-[(3,5-difluoro-4-methyl-6-(3-((phenyl)oxomethyl)phenoxy)pyridin-2-yl)oxy]benzamidine,acetic acid salt, (0.10 g, 0.19 mmol) in methanol was added Pd-C (75mg). After stirring under hydrogen for 2.5 hours, the reaction wasfiltered, concentrated in vacuo, and purified by HPLC as described abovein Example 5 to give3-[(3,5-difluoro-6-(3-((phenyl)hydroxymethyl)phenoxy)-4-methyl-pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; NMR (DMSO-d₆) 9.45 (s,2), 9.35 (s,2), 7.55(m,4), 7.1-7.4 (m,8), 6.95 (m,1), 5.64 (s,1), 2.4 (s,3) ppm.

EXAMPLE 144-Hydroxy-3-[3,5-dichloro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-(1-iminoethyl)pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine,Trifluoroacetic Acid Salt

A. To ethanol (8 mL) was added4-hydroxy-3-[(3,5-dichloro-6-(3-dimethylaminocarbonylphenoxy)-4-(pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine(0.16 g, 0.20 mmol), ethylacetimidate hydrochloride (74 mg, 0.6 mmol),and triethylamine (0.10 g, 1.0 mmol). After stirring for 2 hours, thereaction mixture was concentrated and purified by HPLC as describedabove in Example 5 to give4-hydroxy-3-[(3,5-dichloro-6-(3-dimethylaminocarbonyl-phenoxy)-4-(1-(1-iminoethyl)pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt.

B. In a similar manner, the following compounds were made:

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(1-(1-iminoethyl)pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-(1-iminoethyl)pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; and

4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-(1-iminoethyl)pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt 6922.

C. In a similar manner, the following compounds are made:

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-(1-iminoethyl)pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt;

4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(1-(1-iminoethyl)pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt; and

4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(1-(1-iminoethyl)pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt.

EXAMPLE 15

This example illustrates the preparation of representativepharmaceutical compositions for oral administration containing acompound of the invention, or a pharmaceutically acceptable saltthereof, e.g.,4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,3-dimethoxy-5-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine:

    ______________________________________                                        A.      Ingredients     % wt./wt.                                             ______________________________________                                        Compound of the invention                                                                         20.0%                                                       Lactose 79.5%                                                                 Magnesium stearate  0.5%                                                    ______________________________________                                    

The above ingredients are mixed and dispensed into hard-shell gelatincapsules containing 100 mg each.

    ______________________________________                                        B.      Ingredients     % wt./wt.                                             ______________________________________                                        Compound of the invention                                                                         20.0%                                                       Magnesium stearate  0.9%                                                      Starch  8.6%                                                                  Lactose 79.6%                                                                 PVP (polyvinylpyrrolidone)  0.9%                                            ______________________________________                                    

The above ingredients with the exception of the magnesium stearate arecombined and granulated using water as a granulating liquid. Theformulation is then dried, mixed with the magnesium stearate and formedinto tablets with an appropriate tableting machine.

    ______________________________________                                        C.      Ingredients                                                           ______________________________________                                        Compound of the invention                                                                            0.1     g                                                Propylene glycol 20.0 g                                                       Polyethylene glycol 400 20.0 g                                                Polysorbate 80 1.0 g                                                          Water q.s. 100 mL                                                           ______________________________________                                    

The compound of the invention is dissolved in propylene glycol,polyethylene glycol 400 and polysorbate 80. A sufficient quantity ofwater is then added with stirring to provide 100 mL of the solutionwhich is filtered and bottled.

    ______________________________________                                        D.      Ingredients     % wt./wt.                                             ______________________________________                                        Compound of the invention                                                                         20.0%                                                       Peanut Oil 78.0%                                                              Span 60  2.0%                                                               ______________________________________                                    

The above ingredients are melted, mixed and filled into soft elasticcapsules.

    ______________________________________                                        E.     Ingredients          % wt./wt.                                         ______________________________________                                        Compound of the invention                                                                             1.0%                                                    Methyl or carboxymethyl cellulose 2.0%                                        0.9% saline q.s. 100 mL                                                     ______________________________________                                    

The compound of the invention is dissolved in the cellulose/salinesolution, filtered and bottled for use.

EXAMPLE 16

This example illustrates the preparation of a representativepharmaceutical formulation for parenteral administration containing acompound of the invention, or a pharmaceutically acceptable saltthereof, e.g.,4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-carboxymethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine:

    ______________________________________                                        Ingredients                                                                   ______________________________________                                        Compound of the invention                                                                            0.02    g                                                Propylene glycol 20.0 g                                                       Polyethylene glycol 400 20.0 g                                                Polysorbate 80 1.0 g                                                          0.9% Saline solution q.s. 100 mL                                            ______________________________________                                    

The compound of the invention is dissolved in propylene glycol,polyethylene glycol 400 and polysorbate 80. A sufficient quantity of0.9% saline solution is then added with stirring to provide 100 mL ofthe I.V. solution which is filtered through a 0.2 μ membrane filter andpackaged under sterile conditions.

EXAMPLE 17

This example illustrates the preparation of a representativepharmaceutical composition in suppository form containing a compound ofthe invention, or a pharmaceutically acceptable salt thereof, e.g.,4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methyl-imidazolin-2-yl)phenoxy)-4-(4-ethoxycarbonylmethylpiperazin-1-yl)pyridin-2-yl)oxy]benzamidine:

    ______________________________________                                        Ingredients        % wt./wt.                                                  ______________________________________                                        Compound of the invention                                                                         1.0%                                                        Polyethylene glycol 1000 74.5%                                                Polyethylene glycol 4000 24.5%                                              ______________________________________                                    

The ingredients are melted together and mixed on a steam bath, andpoured into molds containing 2.5 g total weight.

EXAMPLE 18

This example illustrates the preparation of a representativepharmaceutical formulation for insufflation containing a compound of theinvention, or a pharmaceutically acceptable salt thereof, e.g.,4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine:

    ______________________________________                                        Ingredients           % wt./wt.                                               ______________________________________                                        Micronized compound of the invention                                                                 1.0%                                                     Micronized lactose 99.0%                                                    ______________________________________                                    

The ingredients are milled, mixed, and packaged in an insufflatorequipped with a dosing pump.

EXAMPLE 19

This example illustrates the preparation of a representativepharmaceutical formulation in nebulized form containing a compound ofthe invention, or a pharmaceutically acceptable salt thereof, e.g.,4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine:

    ______________________________________                                        Ingredients        % wt./wt.                                                  ______________________________________                                        Compound of the invention                                                                         0.005%                                                      Water 89.995%                                                                 Ethanol 10.000%                                                             ______________________________________                                    

The compound of the invention is dissolved in ethanol and blended withwater. The formulation is then packaged in a nebulizer equipped with adosing pump.

EXAMPLE 20

This example illustrates the preparation of a representativepharmaceutical formulation in aerosol form containing a compound of theinvention, or a pharmaceutically acceptable salt thereof, e.g.,4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine:

    ______________________________________                                        Ingredients        % wt./wt.                                                  ______________________________________                                        Compound of the invention                                                                         0.10%                                                       Propellant 11/12 98.90%                                                       Oleic acid  1.00%                                                           ______________________________________                                    

The compound of the invention is dispersed in oleic acid and thepropellants. The resulting mixture is then poured into an aerosolcontainer fitted with a metering valve.

EXAMPLE 21 (In vitro Assay for Factor Xa, Thrombin and TissuePlasminogen Activator)

This assay demonstrates the activity of the compounds of the inventiontowards factor Xa, thrombin and tissue plasminogen activator. Theactivities were determined as an initial rate of cleavage of the peptidep-nitroanilide by the enzyme. The cleavage product, p-nitroaniline,absorbs at 405 nm with a molar extinction coefficient of 9920 M⁻¹ cm⁻¹.

Reagents and Solutions:

Dimethyl sulfoxide (DMSO) (Baker analyzed grade).

Assay buffer:

50 mM TrisHCl, 150 mM NaCl, 2.5 mM CaCl₂, and 0.1% polyethylene glycol6000, pH 7.5.

Enzymes (Enzyme Research Lab.):

1. Human factor Xa stock solution: 0.281 mg/mL in assay buffer, storedat -80° C. (working solution (2×): 106 ng/mL or 2 nM in assay buffer,prepare prior to use).

2. Human thrombin stock solution: Stored at -80° C. (working solution(2×): 1200 ng/mL or 40 nM in assay buffer, prepare prior to use).

3. Human tissue plasminogen activator (tPA) (Two chains, Sigma) stocksolution: 1 mg/mL, stored at -80° C. (working solution (2×): 1361 ng/mLin assay buffer, prepare prior to use).

Chromogenic substrates (Pharmacia Hepar Inc.):

1. S2222 (FXa assay) stock solution: 6 mM in dH₂ O, store at 4° C.(working solution (4×): 656 μM in assay buffer).

2. S2302 (Thrombin a-say) stock solution: 10 mM in dH₂ O, stored at 4°C. (working solution (4×): 1200 μM in assay buffer).

3. S2288 (tPA assay) stock solution: 10 mM in dH₂ O, stored at 4° C.(working solution (4×): 1484 μM in assay buffer). (All substrate workingsolutions were prepared on assay day 5.)

Standard inhibitor compound stock solution:

5 mM in DMSO, stored at -20° C.

Test compounds (compounds of the invention) stock solutions:

10 mM in DMSO, stored at -20° C.

Assay Procedure:

Assays were performed in 96-well microtiter plates in a total volume of200 μl. Assay components were in final concentration of 50 mM TrisHCl,150 mM NaCl, 2.5 mM CaCl₂, 0.1% polyethylene glycol 6000, pH 7.5, in theabsence or presence of the standard inhibitor or the test compounds andenzyme and substrate at following concentrations: (1) 1 nM factor Xa and164 μM S2222; (2) 20 nM thrombin and 300 μM S2302; and (3) 10 nM tPA and371 μM S2288. Concentrations of the standard inhibitor compound in theassay were from 5 μM to 0.021 μM in 1 to 3 dilution. Concentration ofthe test compounds in the assay typically were from 10 μM to 0.041 μM in1 to 3 dilution. For potent test compounds, the concentrations used inthe factor Xa assay were further diluted 100 fold (100 nM to 0.41 nM) or1000 fold (10 nM to 0.041 nM). All substrate concentrations used areequal to their K_(m) values under the present assay conditions. Assayswere performed at ambient temperature.

The first step in the assay was the preparation of 10 mM test compoundstock solutions in DMSO (for potent test compounds, 10 mM stocksolutions were further diluted to 0.1 or 0.01 mM for the factor Xaassay), followed by the preparation of test compound working solutions(4×) by a serial dilutions of 10 mM stock solutions with Biomek 1000 (orMultiprobe 204) in 96 deep well plates as follows:

(a) Prepare a 40 μM working solution by diluting the 10 mM stock 1 to250 in assay buffer in 2 steps: 1 to 100, and 1 to 2.5.

(b) Make another five serial dilutions (1:3) of the 40 μM solution (600μl for each concentration). A total of six diluted test compoundsolutions were used in the assay.

Standard inhibitor compound (5 mM stock) or DMSO (control) went throughthe same dilution steps as those described above for test compounds.

The next step in the assay was to dispense 50 μl of the test compoundworking solutions (4×) (from 40 μM to 0.164 μM) in duplicate tomicrotiter plates with Biomek or MP204. To this was added 100 μl ofenzyme working solution (2×) with Biomek or MP204. The resultingsolutions were incubated at ambient temperature for 10 minutes.

To the solutions was added 50 μl of substrate working solution (4×) withBiomek or MP204.

The enzyme kinetics were measured at 405 nm at 10 seconds intervals forfive minutes in a THERMOmax plate reader at ambient temperature.

Calculation of K_(i) of the Test Compounds:

Enzyme rates were calculated as mOD/min based on the first two minutesreadings. The IC₅₀ values were determined by fitting the data to thelog-logit equation (linear) or the Morrison equation (non-linear) withan EXCEL spread-sheet. Ki values were then obtained by dividing the IC₅₀by 2. Routinely, Ki(factor Xa) values less than 3 nM were calculatedfrom the Morrison equation.

Compounds of the invention, when tested in this assay, demonstrated theselective ability to inhibit human factor Xa and human thrombin.

EXAMPLE 22 (In vitro Assay for Human Prothrombinase)

This assay demonstrates the ability of the compounds of the invention toinhibit prothrombinase. Prothrombinase (PTase) catalyzes the activationof prothrombin to yield fragment 1.2 plus thrombin with meizothrombin asthe intermediate. This assay is an end point assay. Activity of theprothrombinase is measured by activity of thrombin (one of the reactionproducts) or by the amount of thrombin formed/time based on a thrombinstandard curve (nM vs mOD/min). For determination of IC₅₀ (PTase) of thecompounds of the invention, PTase activity was expressed by thrombinactivity (mOD/min).

Materials:

Enzymes:

1. Human factor Va (Haematologic Technologies Inc., Cat# HCVA-0110)working solution: 1.0 mg/mL in 50% glycerol, 2 mM CaCl₂, stored at -20°C.

2. Human factor Xa (Enzyme Res. Lab. cat# HFXa1011) working solution:0.281 mg/mL in assay buffer (without BSA), stored at -80° C.

3. Human prothrombin (FII) (Enzyme Res. Lab., Cat# HP1002) workingsolution: Diluted FII to 4.85 mg/mL in assay buffer (without BSA),stored at -80° C.

Phospholipid (PCPS) vesicles:

PCPS vesicles (80% PC, 20% PS) were prepared by modification of themethod reported by Barenholz et al., Biochemistry (1977), Vol.16, pp.2806-2810.

Phosphatidyl serine (Avanti Polar Lipids, Inc., Cat#840032):

10 mg/mL in chloroform, purified from brain, stored -20° C. undernitrogen or argon.

Phosphatidyl Choline (Avanti Polar Lipids, Inc., Cat# 850457):

50 mg/ml in chloroform, synthetic 16:0-18:1 Palmitoyl-Oleoyl, stored at-20° C. under nitrogen or argon.

Spectrozyme-TH (American Diagnostica Inc., Cat# 238L, 50 μmoles, storedat room temperature) working solution: Dissolved 50 μmoles in 10 mL dH₂O.

BSA (Sigma Chem Co., Cat# A-7888, FractionV, RIA grade).

Assay buffer: 50 mM TrisHCl, pH 7.5, 150 mM NaCl, 2.5 mM CaCl₂, 0.1% PEG6000 (BDH), 0.05% BSA (Sigma, Fr.V, RIA grade).

For one plate assay, prepare the following working solutions:

1. Prothrombinase complex:

(a) 100 μM PCPS (27.5 μl of PCPS stock (4.36 mM) diluted to final 1200μl with assay buffer.

(b) 25 nM Human factor Va: 5.08 μl of Va stock(1 mg/mL) was diluted tofinal 1200 μl with assay buffer.

(c) 5 μM Human factor Xa: Dilute Xa stock (0.281 mg/mL) 1:1,220,000 withassay buffer. Prepare at least 1200 μl.

Combine equal volumes (1100 μl) of each component in the order of PCPS,Va and Xa. Let stand at ambient temperature for 5 to 10 minutes and useimmediately or store in ice (bring to ambient temperature before use).

2. 6 μM Human prothrombin (FII): dilute 124 μL of FII stock (4.85 mg/mL)to final 1400 μL with assay buffer.

3. 20 mM EDTA/Assay buffer: 0.8 mL of 0.5 M EDTA (pH 8.5) plus 19.2 mLassay buffer.

4. 0.2 mM Spectrozyme-TH/EDTA buffer: 0.44 mL of SPTH stock (5 mM) plus10.56 mL of 20 mM EDTA/assay buffer.

5. Test compounds (compounds of the invention):

Prepare a working solution (5×) from 10 mM stock (DMSO) and make aseries of 1:3 dilution. Compounds were assayed at 6 concentrations induplicate.

Assay conditions and procedure:

Prothrombinase reaction was performed in final 50 μL of mixturecontaining PTase (20 μM PCPS, 5 nM hFVa, and 1 pM hFXa), 1.2 μM humanfactor II and varied concentration of the test compounds (5 μM to 0.021μM or lower concentration range). Reaction was started by addition ofPTase and incubated for 6 minutes at room temperature. Reaction wasstopped by addition of EDTA/buffer to final 10 mM. Activity of thrombin(product) was then measured in the presence of 0.1 mM of Spectrozyme-THas substrate at 405 nm for 5 minutes (10 seconds intervals) at ambienttemperature in a THEROmax microplate reader. Reactions were performed in96-well microtiter plates.

In the first step of the assay, 10 μl of diluted test compound (5×) orbuffer was added to the plates in duplicate. Then 10 μl of prothombin(hFII) (5×) was added to each well. Next 30 μl PTase was added to eachwell, mix for about 30 seconds. The plates were then incubated atambient temperature for 6 minutes.

In the next step, 50 μl of 20 mM EDTA (in assay buffer) was added toeach well to stop the reaction. The resulting solutions were then mixedfor about 10 seconds. Then 100 μl of 0.2 mM spectrozyme was added toeach well. The thrombin reaction rate was then measured at 405 nm for 5minutes at 10 seconds intervals in a Molecular Devices microplatereader.

Calculations:

Thrombin reaction rate was expressed as mOD/min. using OD readings fromthe five minute reaction. IC₅₀ values were calculated with the log-logitcurve fit program.

The compounds of the invention demonstrated the ability to inhibitpro-thrombinase when tested in this assay.

EXAMPLE 23 (In vivo Assay)

The following assay demonstrates the ability of the compounds to act asanti-coagulants.

Male rats (250-330 g) were anesthetized with sodium pentobarbital (90mg/kg, i.p.) and prepared for surgery. The left carotid artery wascannulated for the measurement of blood pressure as well as for takingblood samples to monitor clotting variables (prothrombin time (PT) andactivated partial thromboplastin time (aPTT)). The tail vein wascannulated for the purpose of administering the test compounds (i.e.,the compounds of the invention and standards) and the thromboplastininfusion. The abdomen was opened via a mid-line incision and theabdominal vena cava was isolated for 2-3 cm distal to the renal vein.All venous branches in this 2-3 cm segment of the abdominal vena cavawere ligated. Following all surgery, the animals were allowed tostabilize prior to beginning the experiment. Test compounds wereadministered as an intravenous bolus (t=0). Three minutes later (t=3), a5-minute infusion of thromboplastin was begun. Two minutes into theinfusion (t=5), the abdominal vena cava was ligated at both the proximaland distal ends. The vessel was left in place for 60 minutes, afterwhich it was excised from the animal, slit open, the clot (if any)carefully removed, and weighed. Statistical analysis on the results wasperfomed using a Wilcoxin-matched-pairs signed rank test.

The compounds of the invention, when tested in this assay, demonstratedthe ability to inhibit the clotting of the blood.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made and equivalentsmay be substituted without departing from the true spirit and scope ofthe invention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

What is claimed is:
 1. A compound selected from the group consisting ofthe following formulae: ##STR12## wherein R¹ and R³ are independentlyhydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, --N(R⁸)R⁹,--C(O)OR⁸, --C(O)N(R⁸)R⁹, --C(O)N(R⁸)CH₂ C(O)N(R⁸)R⁹,--N(R⁸)C(O)N(R⁸)R⁹, --N(R⁸)C(O)R⁸, --N(R⁸)S(O)₂ R¹², or--N(R⁸)C(O)N(R⁸)CH₂ C(O)N(R⁸)R⁹ ;R² is (3,4)-piperidinyloxy (optionallysubstituted by one or more substituents selected from the groupconsisting of carboxy, --C(O)N(R⁸)R⁹, alkoxycarbonyl, carboxyalkyl, andalkoxycarbonylalkyl); or R² is 3-pyrrolidinyloxy (optionally substitutedby one or more substituents selected from the group consisting of alkyl,aralkyl, carboxy, carboxyalkyl, --C(O)N(R⁸)R⁹, alkoxycarbonyl andalkoxycarbonylalkyl); R⁴ and R⁷ are independently hydrogen, halo, alkyl,nitro, --OR⁸, --C(O)OR⁸, --C(O)N(R⁸)R⁹, --N(R⁸)R⁹, --N(H)C(O)R⁸, or--N(H)S(O)₂ R¹² ; R⁵ is --C(NH)NH₂, --C(NH)N(H)OR⁸, --C(NH)N(H)C(O)OR¹²,--C(NH)N(H)S(O)₂ R¹², --C(NH)N(H)C(O)N(R⁸)R⁹, or --C(NH)N(H)C(O)R⁸ ; R⁶is (1,2)-imidazolyl (optionally substituted by alkyl), or(1,2)-imidazolinyl (optionally substituted by alkyl); each R⁸ and R⁹ areindependently hydrogen, alkyl, aryl, or aralkyl; and R¹² is alkyl, arylor aralkyl; or a pharmaceutically acceptable salt thereof.
 2. Thecompound of claim 1 selected from formula (I) wherein:R¹ and R³ areindependently hydrogen, fluoro, chloro, haloalkyl, --N(R⁸)R⁹, --C(O)OR⁸,--C(O)N(R⁸)R⁹, --N(R⁸)C(O)N(R⁸)R⁹, --N(R⁸)C(O)R⁸, or --N(R⁸)S(O)₂ R¹² ;R² is (3,4)-piperidinyloxy (optionally substituted by one or moresubstituents selected from the group consisting of carboxy,--C(O)N(R⁸)R⁹, alkoxycarbonyl, carboxyalkyl, and alkoxycarbonylalkyl);or R² is 3-pyrrolidinyloxy (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aralkyl,carboxy, carboxyalkyl, --C(O)N(R⁸)R⁹, alkoxycarbonyl andalkoxycarbonylalkyl); R⁴ is hydrogen, --OR⁸ or --N(R⁸)R⁹ ; R⁵ is--C(NH)NH₂ ; R⁶ is (1,2)-imidazolyl (optionally substituted by alkyl),or (1,2)-imidazolinyl (optionally substituted by alkyl); R⁷ is hydrogen,halo, alkyl, --OR⁸, --C(O)N(R⁸)R9; R⁸ and R⁹ are independently hydrogen,methyl, ethyl or phenyl; and R¹² is methyl, ethyl, phenyl or benzyl. 3.The compound of claim 2 wherein:R¹ and R³ are independently hydrogen,fluoro, chloro, trifluoromethyl, amino, --C(O)N(R⁸)R⁹, or --NHC(O)NHR⁹ ;R² is (3,4)-piperidinyloxy (optionally substituted by one or moresubstituents selected from the group consisting of carboxyalkyl andalkoxycarbonylalkyl); or R² is 3-pyrrolidinyloxy (optionally substitutedby one or more substituents selected from the group consisting ofcarboxy, carboxyalkyl, alkoxycarbonyl and alkoxycarbonylalkyl); R⁴ ishydrogen, amino, hydroxy, or methoxy; R⁵ is --C(NH)NH₂ ; R⁶ is(1,2)-imidazolyl substituted by alkyl, or 2-imidazolinyl substituted byalkyl; R⁷ is hydrogen, methoxy, or hydroxy; and R⁸ and R⁹ areindependently hydrogen, methyl, ethyl, or phenyl.
 4. The compound ofclaim 3 whereinR¹ and R³ are independently hydrogen, fluoro, or chloro;R⁴ is amino, hydrogen, hydroxy or methoxy; R⁶ is (1,2)-imidazolylsubstituted by methyl, or 2-imidazolinyl optionally substituted bymethyl; and R⁷ is hydrogen or hydroxy.
 5. The compound of claim 4whereinR⁴ is hydroxy; R⁶ is (1,2)-imidazolyl substituted by methyl or2-imidazolinyl substituted by methyl; and R⁷ is hydrogen.
 6. Thecompound of claim 1 selected from the group consisting of thefollowing:4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(5-carboxypyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-ethoxycarbonylmethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(5-ethoxycarbonylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-carboxymethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-(1-carboxy-1-methylethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine.7. A pharmaceutical composition useful in treating a human having athrombotic complication associated with myocardial infarction, deep veinthrombosis following orthopedic surgery, transient ischemic attack,coronary artery bypass graft, percutaneous transluminal coronaryangioplasty, acute promyelocytic leukemia, diabetes, multiple myelomas,septic shock, purpura fulminanas, adult respiratory distress syndrome,angina, or aortic valve or vascular prosthesis, which compositioncomprises a therapeutically effective amount of a compound selected fromthe group consisting of the following formulae: ##STR13## wherein R¹ andR³ are independently hydrogen, halo, alkyl, haloalkyl, alkoxy,haloalkoxy, nitro, --N(R⁸)R⁹, --C(O)OR⁸, --C(O)N(R⁸)R⁹, --C(O)N(R⁸)CH₂C(O)N(R⁸)R⁹, --N(R⁸)C(O)N(R⁸)R⁹, --N(R⁸)C(O)R⁸, --N(R⁸)S(O)₂ R¹², or--N(R⁸)C(O)N(R⁸)CH₂ C(O)N(R⁸)R⁹ ;R² is (3,4)-piperidinyloxy (optionallysubstituted by one or more substituents selected from the groupconsisting of carboxy, --C(O)N(R⁸)R⁹, alkoxycarbonyl, carboxyalkyl, andalkoxycarbonylalkyl); or R² is 3-pyrrolidinyloxy (optionally substitutedby one or more substituents selected from the group consisting of alkyl,aralkyl, carboxy, carboxyalkyl, --C(O)N(R⁸)R⁹, alkoxycarbonyl andalkoxycarbonylalkyl); R⁴ and R⁷ are independently hydrogen, halo, alkyl,nitro, --OR⁸, --C(O)OR⁸, --C(O)N(R⁸)R⁹, --N(R⁸)R⁹, --N(H)C(O)R⁸, or--N(H)S(O)₂ R¹² ; ⁵ is --C(NH)NH₂, --C(NH)N(H)OR⁸, --C(NH)N(H)C(O)OR¹²,--C(NH)N(H)S(O)₂ R¹², --C(NH)N(H)C(O)N(R⁸)R⁹, or --C(NH)N(H)C(O)R⁸ ; R⁶is (1,2)-imidazolyl (optionally substituted by alkyl), or(1,2)-imidazolinyl (optionally substituted by alkyl); each R⁸ and R⁹ areindependently hydrogen, alkyl, aryl, or aralkyl; and R¹² is alkyl, arylor aralkyl; or a pharmaceutically acceptable salt thereof in a admixturewith a pharmaceutically acceptable carrier.
 8. A method of treating ahuman having a thrombotic complication associated with myocardialinfarction, deep vein thrombosis following orthopedic surgery, transientischemic attack, coronary artery bypass graft, percutaneous transluminalcoronary angioplasty, acute promyelocytic leukemia, diabetes, multiplemyelomas, septic shock, purpura fulminanas, adult respiratory distresssyndrome, angina, or aortic valve or vascular prosthesis, which methodcomprises administering to a human in need thereof a therapeuticallyeffective amount of a compound selected from the group consisting of thefollowing formulae: ##STR14## wherein R¹ and R³ are independentlyhydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, --N(R⁸)R⁹,--C(O)OR⁸, --C(O)N(R⁸)R⁹, --C(O)N(R⁸)CH₂ C(O)N(R⁸)R⁹,--N(R⁸)C(O)N(R⁸)R⁹, --N(R⁸)C(O)R⁸, --N(R⁸)S(O)₂ R¹², or--N(R⁸)C(O)N(R⁸)CH₂ C(O)N(R⁸)R⁹ ;R² is (3,4)-piperidinyloxy (optionallysubstituted by one or more substituents selected from the groupconsisting of carboxy, --C(O)N(R⁸)R⁹, alkoxycarbonyl, carboxyalkyl, andalkoxycarbonylalkyl); or R² is 3-pyrrolidinyloxy (optionally substitutedby one or more substituents selected from the group consisting of alkyl,aralkyl, carboxy, carboxyalkyl, --C(O)N(R⁸)R⁹, alkoxycarbonyl andalkoxycarbonylalkyl); R⁴ and R⁷ are independently hydrogen, halo, alkyl,nitro, --OR⁸, --C(O)OR⁸, --C(O)N(R⁸)R⁹, --N(R⁸)R⁹, --N(H)C(O)R⁸, or--N(H)S(O)₂ R¹² ; R⁵ is --C(NH)NH₂, --C(NH)N(H)OR⁸, --C(NH)N(H)C(O)OR¹²,--C(NH)N(H)S(O)₂ R¹², --C(NH)N(H)C(O)N(R⁸)R⁹, or --C(NH)N(H)C(O)R⁸ ; R⁶is (1,2)-imidazolyl (optionally substituted by alkyl), or(1,2)-imidazolinyl (optionally substituted by alkyl); each R⁸ and R⁹ areindependently hydrogen, alkyl, aryl, or aralkyl; and R¹² is alkyl, arylor aralkyl; or a pharmaceutically acceptable salt thereof.